cGAS antagonist compounds

ABSTRACT

Disclosed are novel compounds of Formula I that are cGAS antagonists, methods of preparation of the compounds, pharmaceutical compositions comprising the compounds, and their use in medical therapy.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of International Application No.PCT/US17/026019, filed on Apr. 4, 2017, which claims the benefit of U.S.Provisional Application No. 62/318,435, filed Apr. 5, 2016, and U.S.Provisional Application No. 62/355,403, filed Jun. 28, 2016, the entirecontents of each of which is hereby incorporated by reference herein.

TECHNICAL FIELD

The present invention provides novel cGAS antagonist compounds,pharmaceutical compositions thereof, and their use in medical therapy.In particular, the compounds of the invention are useful for treatinginflammatory, allergic, autoimmune, and infectious diseases. Thecompounds can also be used for the treatment of senescence- orage-related diseases, such as neurodegenerative diseases, cardiovasculardiseases, liver and renal diseases, cancer and premature aging.

BACKGROUND

Cytosolic DNA induces type-I interferons and other cytokines that areimportant for immune defense against microbial infections and malignantcells but can also result in autoimmunity. This DNA signaling pathwayrequires the adaptor protein STING (Stimulator of Interferon Genes) andthe transcription factors NF-κB and IRF3, but the mechanism of DNAsensing was unclear until recently. WO 2014099824 to The University ofTexas disclosed that mammalian cytosolic extracts synthesizedcyclic-GMP-AMP (cGAMP) in vitro from ATP and GTP in the presence of DNAbut not RNA. DNA transfection or DNA virus infection of mammalian cellsalso triggered cGAMP production. cGAMP bound to STING, leading to theactivation of IRF3 and induction of type-I interferons includinginterferon-β (IFN-β). Thus, cGAMP represents the first cyclicdi-nucleotide in metazoa and it functions as an endogenous secondmessenger that triggers interferon production in response to cytosolicDNA.

Through biochemical fractionation and quantitative mass spectrometry,the inventors on WO 2014099824 also identified a cGAMP synthase (cGAS),which belongs to the nucleotidyltransferase family. Overexpression ofcGAS activated the transcription factor IRF3 and induced IFN in aSTING-dependent manner. Knockdown of cGAS inhibited IRF3 activation andIFN induction by DNA transfection or DNA virus infection. cGAS bound toDNA in the cytoplasm and catalyzed cGAMP synthesis. These resultsindicate that cGAS is a cytosolic DNA sensor that induces interferons byproducing the second messenger cGAMP.

Several additional patents applications in this field have henceforthpublished:

US20140205653 and US 20140341976 to Aduro Biotech disclosecyclic-di-nucleotide (CDN) compounds that activate and inhibit STING,respectively. In particular, the CDNs of the invention are provided inthe form of a composition comprising one or more cyclic purinedinucleotides which activate or inhibit STING-dependent TBK1 activationand the resulting production of type I interferon.

WO 2015077354 A1 to The University of Chicago discloses Methods andcompositions for treating cancer by intratumorally administering astimulator of interferon genes (STING) agonist are disclosed herein. Insome embodiments, there are provided compositions and methods concerningmethods for treating cancer in a subject comprising administering to thesubject an effective amount of a stimulator of interferon genes (STING)agonist, wherein the STING agonist is administered intratumorally.

WO 2015161762 to Fudan University discloses the use of cyclicdinucleotide cGAMP for preparing antitumor drugs, wherein the tumor isgastric cancer, lung cancer, colon cancer, liver cancer, prostate canceror pancreatic cancer. cGAMP was shown to inhibit the growth of humantumor cell lines in immune compromised mice.

WO 2015185565 to GlaxoSmithKline discloses a cyclic dinucleotide analogor a pharmaceutically acceptable salt and tautomers thereof,compositions, combinations and medicaments containing said compounds andprocesses for their preparation. The invention also relates to the useof said compounds, combinations, compositions and medicaments, in thetreatment of diseases and conditions in which modulation of STING(Stimulator of Interferon Genes) is beneficial, for exampleinflammation, allergic and autoimmune diseases, infectious diseases,cancer and as vaccine adjuvants.

WO 2014179335 to Memorial Sloan Kettering Cancer Center disclosescompositions, methods, kits, and assays related to the use and/orexploitation of isomers of cGAMP as well as the structure of the enzymecGAS.

To our knowledge, no specific antagonist of cGAS has been reported orpatented. Genetic experiments have demonstrated that deletion of cGASrescues lethal autoimmune diseases in mouse models (Gao et al., 2015,PNAS 112, E5699), suggesting that cGAS inhibitors may be used for thetreatment of human autoimmune and autoinflammatory diseases, includingsystemic lupus erythematosus (SLE), scleroderma, psoriasis, AicardiGoutieres syndrome, Sjogren's syndrome, rheumatoid arthritis,inflammataory bowel diseases, multiple sclerosis, diabetes,cardiovascular, and neurodegenerative diseases. In addition, because DNAdamage causes senescence and induces proinflammatory cytokines, cGASinhibitors may be used to treat senescence- or age-related diseases.There is an urgent need to develop first-in-class, potent and specificchemical inhibitors of cGAS for the treatment of these debilitatinghuman diseases.

SUMMARY OF THE INVENTION

Formula I Encompasses Formula Ia-Id.

In one aspect, the invention provides a compound of Formula Ia, or apharmaceutically acceptable salt thereof,

wherein:

X is NH or S;

Y is O or S;

Z is O, S, CHR^(1a) or NR^(1a);

-   -   R^(1a) is hydrogen, C₁₋₆alkyl, or C₁₋₆alkyl selectively        functionalized with one or more halogen, thiol, hydroxyl,        carbonyl, carboxyl, carbonyloxyl, C₁₋₆alkoxy, C₁₋₆hydroxyalkoxy,        amino, C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, or azido groups; G is        N or C;    -   if G is N, R¹ is hydrogen C₁₋₆alkyl, or C₁₋₆alkyl selectively        functionalized with one or more halogen, thiol, hydroxyl,        carbonyl, carboxyl, carbonyloxyl, C₁₋₆alkoxy, C₁₋₆hydroxyalkoxy,        amino, C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, or azido groups,    -   if G is N and if Z includes R^(1a), R¹-R^(1a) is connected as a        —CH₂CH₂—, —CH₂CH₂CH₂—, —CH═CH—, —C(CH₃)═CH—, or —CH═C(CH₃)—        group; and    -   if G is C and if Z includes R^(1a), R¹-R^(1a) is connected as a        ═CH—CH═CH—, ═N—CH═CH—, or ═CH—N═CH— group;

R¹ is hydrogen or C₁₋₆alkyl, or R¹-R^(1a) are connected form a —CH₂CH₂—,—CH₂CH₂CH₂—, —CH═CH—, —C(CH₃)═CH—, or —CH═C(CH₃)— group or together withcarbon or nitrogen atoms to which they are attached form a pyridine,pyrimidine or pyrazine ring;

R² is hydrogen, halo, C₁₋₆alkyl, or C₁₋₆alkyl selectively functionalizedwith one or more halogen, thiol, hydroxyl, carbonyl, carboxyl,carbonyloxyl, C₁₋₆alkoxy, C₁₋₆hydroxyalkoxy, amino, C₁₋₆alkylamino,di(C₁₋₆alkyl)amino, or azido groups;

R^(2a) is phenyl or a heteroaryl group selected from the groupconsisting of imidazolyl, pyridyl, pyridizinyl, pyrimidinyl, andpyrazinyl, wherein the phenyl or heterocyclic group is optionallysubstituted with 1-4 substituents independently selected from the groupconsisting of halogen, —SR^(3a), —S(O)R^(3a), —OR^(3a), —OCH₂R^(3b),—OCH(CH₃)R^(3b), —OC(O)NHR^(3a), —NR^(3a)R⁴, —NHSO₂R^(3a), azido, —CHO,—CO₂R^(3a), cyano, C₁₋₆alkyl or —CR^(5a)R^(6a)R^(7a), C₂₋₆alkenyl,—C(R^(5a))═C(R^(8a))(R^(9a)), C₂₋₆alkynyl, and —C≡CR^(8a);

-   -   R^(3a), R^(3b), and R^(4a) are independently hydrogen, phenyl,        naphthyl, pyridyl, pyrimidinyl, imidazolyl, 1,2,3-triazolyl,        quinolinyl, isoquinolinyl, thiazolyl, tetrazolyl groups,        C₁₋₆alkyl, cyclic —(C₁₋₈alkyl)-, cyclic —(C₁₋₆oxaalkyl)-, cyclic        —(C₁₋₆azaalkyl)-, C₂₋₆alkenyl, or C₂₋₆alkynyl;        -   wherein the phenyl, naphthyl, pyridyl, pyrimidinyl,            imidazolyl, 1,2,3-triazolyl, quinolinyl, isoquinolinyl, and            thiazolyl, tetrazolyl groups are optionally substituted with            1-3 substituents independently selected from the group            consisting of halogen, thiol, C₁₋₆alkyl thioether, C₁₋₆alkyl            sulfoxide, C₁₋₆alkyl, C₁₋₆alkoxyl, amino, C₁₋₆alkylamino,            C₁₋₆dialkylamino, C₁₋₆alkyl sulfonamide, azido, —CHO, —CO₂H,            C₁₋₆alkyl carboxylate, cyano, C₂₋₆alkenyl, and C₂₋₆alkynyl            group; and the C₁₋₆alkyl, cyclic —(C₁₋₈alkyl)-, cyclic            —(C₁₋₆oxaalkyl)-, cyclic —(C₁₋₆azaalkyl)-, C₂₋₆alkenyl, and            C₂₋₆alkynyl groups are selectively functionalized with one            or more halogen, thiol, hydroxyl, carbonyl, carboxyl,            carbonyloxyl, C₁₋₆alkoxy, C₁₋₆hydroxyalkoxy, amino,            C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, azido, piperidinyl,            phenyl, naphthyl, pyridyl, pyrimidinyl, imidazolyl,            1,2,3-triazolyl, quinolinyl, isoquinolinyl, thiazolyl, or            tetrazolyl groups; and    -   R^(5a), R^(6a), R^(7a), R^(8a) and R^(9a) are independently        hydrogen, phenyl, naphthyl, pyridyl, pyrimidinyl, imidazolyl,        1,2,3-triazolyl, quinolinyl, isoquinolinyl, thiazolyl,        tetrazolyl groups, C₁₋₆alkyl, cyclic —(C₁₋₈alkyl)-, cyclic        —(C₁₋₆oxaalkyl)-, cyclic —(C₁₋₆azaalkyl)-, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₁₋₆alkoxyl, cyclic —(C₁₋₈alkoxyl)-, cyclic        —(C₁₋₆oxaalkoxyl)-, cyclic —(C₁₋₆azaalkoxyl)-;        -   wherein the phenyl, naphthyl, pyridyl, pyrimidinyl,            imidazolyl, 1,2,3-triazolyl, quinolinyl, isoquinolinyl, and            thiazolyl, tetrazolyl groups are optionally substituted with            1-3 substituents independently selected from the group            consisting of halogen, thiol, C₁₋₆alkyl thioether, C₁₋₆alkyl            sulfoxide, C₁₋₆alkyl, C₁₋₆alkoxyl, amino, C₁₋₆alkylamino,            C₁₋₆dialkylamino, C₁₋₆alkyl sulfonamide, azido, —CHO, —CO₂H,            C₁₋₆alkyl carboxylate, cyano, C₂₋₆alkenyl, and C₂₋₆alkynyl            group, and the C₁₋₆alkyl, cyclic —(C₁₋₈alkyl)-, cyclic            —(C₁₋₆oxaalkyl)-, cyclic —(C₁₋₄azaalkyl)-, C₂₋₆alkenyl, and            C₂₋₆alkynyl groups are selectively functionalized with one            or more halogen, thiol, hydroxyl, carbonyl, carboxyl,            carbonyloxyl, C₁₋₆alkoxy, C₁₋₆hydroxyalkoxy, amino,            C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, azido, piperidinyl,            phenyl, naphthyl, pyridyl, pyrimidinyl, imidazolyl,            1,2,3-triazolyl, quinolinyl, isoquinolinyl, thiazolyl, or            tetrazolyl groups.

In one embodiment, X is S, Y is O or S, and R^(2a) is a imidazolyl,pyridyl, pyridizinyl, pyrimidinyl, or pyrazinyl group with 0-3substituents independently selected from the group consisting ofhalogen, —SR^(3a), —S(O)R^(3a), —OR^(3a), —OCH₂R^(3b), —OCH(CH₃)R^(3b),—OC(O)NHR^(3a), —NR^(3a)R^(4a), —NHSO₂R^(3a), azido, carbonyl, —CHO,CO₂R^(3a), cyano, C₁₋₆alkyl or —CR^(5a)R^(6a)R^(7a), C₂₋₆alkeny,—C(R^(5a))═C(R^(8a))(R^(9a)), C₂₋₆alkynyl, and —C≡CR^(8a).

In another embodiment, X is S, Y is O or S, and R^(2a) is imidazolylgroup with 0-3 substituents independently selected from the groupconsisting of halogen, —SR^(3a), —S(O)R^(3a), —OR^(3a), —OCH₂R^(3b),—OCH(CH₃)R^(3b), —OC(O)NHR^(3a), —NR^(3a)R^(4a), —NHSO₂R^(3a), azido,—CHO, CO₂R^(3a), cyano, C₁₋₆alkyl or —CR^(5a)R^(6a)R^(7a), C₂₋₆alkeny,—C(R^(5a))═C(R^(8a))(R^(9a)), C₂₋₆alkynyl, and —C≡CR^(8a)

In another embodiment, X is S, Y is O or S, and R^(2a) is pyridyl groupwith 0-3 substituents independently selected from the group consistingof halogen, —SR^(3a), —S(O)R^(3a), —OR^(3a), —OCH₂R^(3b),—OCH(CH₃)R^(3b), —OC(O)NHR^(3a), —NR^(3a)R^(4a), —NHSO₂R^(3a), azido,—CHO, CO₂R^(3a), cyano, C₁₋₆alkyl or —CR^(5a)R^(6a)R^(7a), C₂₋₆alkeny,—C(R^(5a))═C(R^(8a))(R^(9a)), C₂₋₆alkynyl, and —C≡CR^(8a).

In another embodiment, X is S, Y is O or S, and R^(2a) is pyridizinylgroup with 0-3 substituents independently selected from the groupconsisting of halogen, —SR^(3a), —S(O)R^(3a), —OR^(3a), —OCH₂R^(3b),—OCH(CH₃)R^(3b), —OC(O)NHR^(3a), —NR^(3a)R^(4a), —NHSO₂R^(3a), azido,—CHO, CO₂R^(3a), cyano, C₁₋₆alkyl or —CR^(5a)R^(6a)R^(7a), C₂₋₆alkeny,—C(R^(5a))═C(R^(8a))(R^(9a)), C₂₋₆alkynyl, and —C≡CR^(8a).

In another embodiment, X is S, Y is O or S, and R^(2a) is pyrimidinylgroup with 0-3 substituents independently selected from the groupconsisting of halogen, —SR^(3a), —S(O)R^(3a), —OR^(3a), —OCH₂R^(3b),—OCH(CH₃)R^(3b), —OC(O)NHR^(3a), —NR^(3a)R^(4a), —NHSO₂R^(3a), azido,—CHO, CO₂R^(3a), cyano, C₁₋₆alkyl or —CR^(5a)R^(6a)R^(7a), C₂₋₆alkeny,—C(R^(5a))═C(R^(8a))(R^(9a)), C₂₋₆alkynyl, and —C≡CR^(8a).

In another embodiment, X is S, Y is O or S, and R^(2a) is pyrazinylgroup with 0-3 substituents independently selected from the groupconsisting of halogen, —SR^(3a), —S(O)R^(3a), —OR^(3a), —OCH₂R^(3b),—OCH(CH₃)R^(3b), —OC(O)NHR^(3a), —NR^(3a)R^(4a), —NHSO₂R^(3a), azido,—CHO, CO₂R^(3a), cyano, C₁₋₆alkyl or —CR^(5a)R^(6a)R^(7a), C₂₋₆alkeny,—C(R^(5a))═C(R^(8a))(R^(9a)), C₂₋₆alkynyl, and —C≡CR^(8a).

In another embodiment, X is S, Y is O or S, and R^(2a) is phenyl groupwith 0-4 substituents independently selected from the group consistingof halogen, —SR^(3a), —S(O)R^(3a), —OR^(3a), —OCH₂R^(3b),—OCH(CH₃)R^(3b), —OC(O)NHR^(3a), —NR^(3a)R^(4a), —NHSO₂R^(3a), azido,—CHO, CO₂R^(3a), cyano, C₁₋₆alkyl or —CR^(5a)R^(6a)R^(7a), C₂₋₆alkeny,—C(R^(5a))═C(R^(8a))(R^(9a)), C₂₋₆alkynyl, and —C≡CR^(8a).

In another embodiment, X is S, Y is O or S, G is N, and R¹ is hydrogenC₁₋₆alkyl, or C₁₋₆alkyl selectively functionalized with one or morehalogen, thiol, hydroxyl, carbonyl, carboxyl, carbonyloxyl, C₁₋₆alkoxy,C₁₋₆hydroxyalkoxy, amino, C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, or azidogroups.

In another embodiment, X is S, Y is O or S, G is N, and R¹-R^(1a) isconnected as a —CH₂CH₂—, —CH₂CH₂CH₂—, —CH═CH—, —C(CH₃)═CH—, or—CH═C(CH₃)— group.

In another embodiment, The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein X is S, Y is O or S, G is C, Z isNR^(1a), and R¹-R^(1a) is connected as a ═CH—CH═CH—, ═N—CH═CH—, or═CH—N═CH— group.

In another embodiment, X is S, Y is O or S, and R² is hydrogen, halogen,C₁₋₆alkyl, or C₁₋₆alkyl selectively functionalized with one or morehalogen, thiol, hydroxyl, carbonyl, carboxyl, carbonyloxyl, C₁₋₆alkoxy,C₁₋₆hydroxyalkoxy, amino, C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, or azidogroups.

In another embodiment, R² is hydrogen, Cl, Br, or methyl

In another embodiment, the invention provides a compound of Formula Ib,or a pharmaceutically acceptable salt thereof,

wherein:

X is NH or S;

Y is O or S;

Z is O, S, CHR^(8a) or NR;

-   -   R^(1a) is hydrogen, C₁₋₆alkyl, or C₁₋₆alkyl selectively        functionalized with one or more halogen, thiol, hydroxyl,        carbonyl, carboxyl, carbonyloxyl, C₁₋₆alkoxy, C₁₋₆hydroxyalkoxy,        amino, C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, or azido groups; G is        N or C;    -   if G is N, R¹ is hydrogen C₁₋₆alkyl, or C₁₋₆alkyl selectively        functionalized with one or more halogen, thiol, hydroxyl,        carbonyl, carboxyl, carbonyloxyl, C₁₋₆alkoxy, C₁₋₆hydroxyalkoxy,        amino, C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, or azido groups, or        R¹-R^(1a) is connected as a —CH₂CH₂—, —CH₂CH₂CH₂—, —CH═CH—,        —C(CH₃)—CH—, or —CH═C(CH₃)— group; and if G is C, R¹-R^(1a) is        connected as a ═CH—CH═CH—, ═N—CH═CH—, or ═CH—N═CH— group;

R¹ is hydrogen or C₁₋₆alkyl, or R¹-R^(1a) are connected form a —CH₂CH₂—,—CH₂CH₂CH₂—, —CH═CH—, —C(CH₃)═CH—, or —CH═C(CH₃)— group or together withcarbon or nitrogen atoms to which they are attached form a pyridine,pyrimidine or pyrazine ring;

R² is hydrogen, halo, C₁₋₆alkyl, or C₁₋₆alkyl selectively functionalizedwith one or more halogen, thiol, hydroxyl, carbonyl, carboxyl,carbonyloxyl, C₁₋₆alkoxy, C₁₋₆hydroxyalkoxy, amino, C₁₋₆alkylamino,di(C₁₋₆alkyl)amino, or azido groups;

R³, R⁵, and R⁶ are independently hydrogen, halogen, —SR^(3a),—S(O)R^(3a), —OR^(3a), —OCH₂R^(3b), —OCH(CH₃)R^(3b), —OC(O)NHR^(3a),—NR^(3a)R^(4a), —NHSO₂R^(3a), azido, —CHO, CO₂R^(3a), cyano, C₁₋₆alkylor —CR^(5a)R^(6a)R^(7a), C₂₋₆alkeny, —C(R^(5a))═C(R^(8a))(R^(9a)),C₂₋₆alkynyl, —C≡CR^(8a), or R²-R³ is connected as a —CH₂CH₂— or—CH₂CH₂CH₂— group;

-   -   R^(3a), R^(3b), and R⁴⁸ are independently hydrogen, phenyl,        naphthyl, pyridyl, pyrimidinyl, imidazolyl, 1,2,3-triazolyl,        quinolinyl, isoquinolinyl, thiazolyl, tetrazolyl groups,        C₁₋₆alkyl, cyclic —(C₁₋₈alkyl)-, cyclic —(C₁₋₆oxaalkyl)-, cyclic        —(C₁₋₆azaalkyl)-, C₂₋₆alkenyl, C₂₋₆alkynyl;        -   wherein the phenyl, naphthyl, pyridyl, pyrimidinyl,            imidazolyl, 1,2,3-triazolyl, quinolinyl, isoquinolinyl, and            thiazolyl, tetrazolyl groups are optionally substituted with            1-3 substituents independently selected from the group            consisting of halogen, thiol, C₁₋₆alkyl thioether, C₁₋₆alkyl            sulfoxide, C₁₋₆alkyl, C₁₋₆alkoxyl, amino, C₁₋₆alkylamino,            C₁₋₆dialkylamino, C₁₋₆alkyl sulfonamide, azido, —CHO, —CO₂H,            C₁₋₆alkyl carboxylate, cyano, C₂₋₆alkeny, and C₂₋₆alkynyl            group; and the C₁₋₆alkyl, cyclic —(C₁₋₆alkyl)-, cyclic            —(C₁₋₆oxaalkyl)-, cyclic —(C₁₋₆azaalkyl)-, C₂₋₆alkenyl, and            C₂₋₆alkynyl groups are selectively functionalized with one            or more halogen, thiol, hydroxyl, carbonyl, carboxyl,            carbonyloxyl, C₁₋₆alkoxy, C₁₋₆hydroxyalkoxy, amino,            C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, azido, piperidinyl,            phenyl, naphthyl, pyridyl, pyrimidinyl, imidazolyl,            1,2,3-triazolyl, quinolinyl, isoquinolinyl, thiazolyl, or            tetrazolyl groups;

R⁴ is hydrogen or halogen.

In another embodiment, X is S, Y is O or S, G is N, and R¹ is hydrogenC₁₋₆alkyl, or C₁₋₆alkyl selectively functionalized with one or morehalogen, thiol, hydroxyl, carbonyl, carboxyl, carbonyloxyl, C₁₋₆alkoxy,C₁₋₆hydroxyalkoxy, amino, C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, or azidogroups.

In another embodiment, X is S, Y is O or S, G is N, and R¹-R^(1a) isconnected as a —CH₂CH₂—, —CH₂CH₂CH₂—, —CH═CH—, —C(CH₃)═CH—, or—CH═C(CH₃)— group.

In another embodiment, X is S, Y is O or S, G is C, Z is NR^(1a), andR¹-R^(1a) is connected as a ═CH—CH═CH—, ═N—CH═CH—, or ═CH—N═CH— group.

In another embodiment, R² is hydrogen, Cl, Br, or methyl.

In another embodiment, X is S, Y is O or S, G is N, and R¹ is hydrogenC₁₋₆alkyl, or C₁₋₆alkyl selectively functionalized with one or morehalogen, thiol, hydroxyl, carbonyl, carboxyl, carbonyloxyl, C₁₋₆alkoxy,C₁₋₆hydroxyalkoxy, amino, C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, or azidogroups.

In another embodiment, X is S, Y is O or S, G is C, Z is NR^(1a), andR¹-R^(1a) is connected as a ═CH—CH═CH—, ═N—CH═CH—, or ═CH—N═CH— group.

In another embodiment, the invention provides a compound of Formula Ic,or a pharmaceutically acceptable salt thereof,

wherein:

X is NH or S;

Y is O or S;

Z is O, S, CHR^(1a) or NR^(1a);

-   -   R^(1a) is hydrogen, C₁₋₆alkyl, or C₁₋₆alkyl selectively        functionalized with one or more halogen, thiol, hydroxyl,        carbonyl, carboxyl, carbonyloxyl, C₁₋₆alkoxy, C₁₋₆hydroxyalkoxy,        amino, C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, or azido groups;

G is N or C;

-   -   if G is N, R¹ is hydrogen C₁₋₆alkyl, or C₁₋₆alkyl selectively        functionalized with one or more halogen, thiol, hydroxyl,        carbonyl, carboxyl, carbonyloxyl, C₁₋₆alkoxy, C₁₋₆hydroxyalkoxy,        amino, C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, or azido groups, or        R¹-R^(1a) is connected as a —CH₂CH₂—, —CH₂CH₂CH₂—, —CH═CH—,        —C(CH₃)═CH— or —CH═C(CH₃)— group; and if G is C, R¹-R^(1a) is        connected as a ═CH—CH═CH—, ═N—CH═CH—, or ═CH—N═CH— group;

W is OR^(10a) or NHR^(10a);

-   -   wherein R^(10a) is hydrogen, C₁₋₆alkyl, C₁₋₆alkyl selectively        functionalized with one or more halogen, thiol, hydroxyl,        carbonyl, carboxyl, carbonyloxyl, C₁₋₆alkoxy, C₁₋₆hydroxyalkoxy,        amino, C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, or azido groups, or        R^(10a)-R⁶ is connected as a —CH₂—CH₂—, —CH═CH—, —N═CH—, or        —CH═N— group;

R² is hydrogen, halo, C₁₋₆alkyl, or C₁₋₆alkyl selectively functionalizedwith one or more halogen, thiol, hydroxyl, carbonyl, carboxyl,carbonyloxyl, C₁₋₆alkoxy, C₁₋₆hydroxyalkoxy, amino, C₁₋₆alkylamino,di(C₁₋₆alkyl)amino, or azido groups;

R³ and R⁶ are independently hydrogen, halogen, —SR^(3a), —S(O)R^(3a),—OR^(3a), —OCH₂R^(3b), —OCH(CH₃)R^(3b), —OC(O)NHR^(3a), —NR^(3a)R^(4a),—NHSO₂R^(3a), azido, —CHO, CO₂R^(3a), cyano, C₁₋₆alkyl or—CR^(5a)R^(6a)R^(7a), C₂₋₆alkeny, —C(R^(5a))═C(R^(8a))(R^(9a)),C₂₋₆alkynyl, —C≡CR^(8a), or R²-R³ are connected as a —CH₂CH₂— or—CH₂CH₂CH₂— group;

-   -   R^(3a), R^(3b), and R^(4a) are independently hydrogen, phenyl,        naphthyl, pyridyl, pyrimidinyl, imidazolyl, 1,2,3-triazolyl,        quinolinyl, isoquinolinyl, thiazolyl, tetrazolyl groups,        C₁₋₆alkyl, cyclic —(C₁₋₈alkyl)-, cyclic —(C₁₋₆oxaalkyl)-, cyclic        —(C₁₋₆azaalkyl)-, C₂₋₆alkenyl, C₂₋₆alkynyl;        -   wherein the phenyl, naphthyl, pyridyl, pyrimidinyl,            imidazolyl, 1,2,3-triazolyl, quinolinyl, isoquinolinyl,            thiazolyl, or tetrazolyl groups are optionally substituted            with 1-3 substituents independently selected from the group            consisting of halogen, thiol, C₁₋₆alkyl thioether, C₁₋₆alkyl            sulfoxide, C₁₋₆ alkyl, C₁₋₆alkoxyl, amino, C₁₋₆alkylamino,            C₁₋₆dialkylamino, C₁₋₆alkyl sulfonamide, azido, —CHO, —CO₂H,            C₁₋₆alkyl carboxylate, cyano, C₂₋₆alkeny, and C₂₋₆alkynyl            group; and the C₁₋₆alkyl, cyclic —(C₁₋₆alkyl)-, cyclic            —(C₁₋₆oxaalkyl)-, cyclic —(C₁₋₆azaalkyl)-, C₂₋₆alkenyl, or            C₂₋₆alkynyl groups are selectively functionalized with one            or more halogen, thiol, hydroxyl, carbonyl, carboxyl,            carbonyloxyl, C₁₋₆alkoxy, C₁₋₆hydroxyalkoxy, amino,            C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, azido, piperidinyl,            phenyl, naphthyl, pyridyl, pyrimidinyl, imidazolyl,            1,2,3-triazolyl, quinolinyl, isoquinolinyl, thiazolyl, or            tetrazolyl groups;

R⁴ is hydrogen or halogen

In another embodiment, X is S, Y is O or S, Z is O or S, G is N, and R¹is hydrogen C₁₋₆alkyl, or C₁₋₆alkyl selectively functionalized with oneor more halogen, thiol, hydroxyl, carbonyl, carboxyl, carbonyloxyl,C₁₋₆alkoxy, C₁₋₆hydroxyalkoxy, amino, C₁₋₆alkylamino,di(C₁₋₆alkyl)amino, or azido groups.

In another embodiment, X is S, Y is O or S, G is N, Z is NR^(1a), andR¹-R^(1a) is connected as a —CH₂CH₂—, —CH₂CH₂CH₂—, —CH═CH—, —C(CH₃)═CH—,or —CH═C(CH₃)— group.

In another embodiment, X is S, Y is O or S, G is C, Z is NR^(1a), andR¹-R^(1a) is connected as a ═CH—CH═CH—, ═N—CH═CH—, or ═CH—N═CH— group.

In another embodiment, R² is hydrogen, Cl, Br, or methyl.

In another embodiment, the invention provides a compound of Formula Id,or a pharmaceutically acceptable salt thereof,

wherein:

Z is O, S, CHR^(1a) or NR^(1a);

-   -   R^(1a) is hydrogen, C₁₋₆alkyl, or C₁₋₆alkyl selectively        functionalized with one or more halogen, thiol, hydroxyl,        carbonyl, carboxyl, carbonyloxyl, C₁₋₆alkoxy, C₁₋₆hydroxyalkoxy,        amino, C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, or azido groups;

G is N or C;

-   -   if G is N, R¹ is hydrogen C₁₋₆alkyl, or C₁₋₆alkyl selectively        functionalized with one or more halogen, thiol, hydroxyl,        carbonyl, carboxyl, carbonyloxyl, C₁₋₆alkoxy, C₁₋₆hydroxyalkoxy,        amino, C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, or azido groups, or        R¹-R^(1a) is connected as a —CH₂CH₂—, —CH₂CH₂CH₂—, —CH═CH—,        —C(CH₃)—CH— or —CH═C(CH₃)— group; and if G is C, R¹-R^(1a) is        connected as a ═CH—CH═CH—, ═N—CH═CH—, or ═CH—N═CH— group;

R³ and R⁴ are independently hydrogen or halogen;

R⁶ is hydrogen, halogen, —SR^(3a), —S(O)R^(3a), —OR^(3a), —OCH₂R^(3b),—OCH(CH₃)R^(3b), —OC(O)NHR^(3a), —NR^(3a)R^(4a), —NHSO₂R^(3a), azido,—CHO, CO₂R^(3a), cyano, C₁₋₆alkyl or —CR^(5a)R^(6a)R^(7a), C₂₋₆alkeny,—C(R^(5a))═C(R^(8a))(R^(9a)), C₂₋₆alkynyl, —C≡CR^(8a), or R²-R³ areconnected as a —CH₂CH₂— or —CH₂CH₂CH₂— group;

-   -   R^(3a), R^(3b), and R^(4a) are independently hydrogen, phenyl,        naphthyl, pyridyl, pyrimidinyl, imidazolyl, 1,2,3-triazolyl,        quinolinyl, isoquinolinyl, thiazolyl, tetrazolyl groups,        C₁₋₆alkyl, cyclic —(C₁₋₈alkyl)-, cyclic —(C₁₋₆oxaalkyl)-, cyclic        —(C₁₋₆azaalkyl)-, C₂₋₆alkenyl, C₂₋₆alkynyl;        -   wherein the phenyl, naphthyl, pyridyl, pyrimidinyl,            imidazolyl, 1,2,3-triazolyl, quinolinyl, isoquinolinyl,            thiazolyl, or tetrazolyl groups are optionally substituted            with 1-3 substituents independently selected from the group            consisting of halogen, thiol, C₁₋₆alkyl thioether, C₁₋₆alkyl            sulfoxide, C₁₋₆alkyl, C₁₋₆alkoxyl, amino, C₁₋₆alkylamino,            C₁₋₆dialkylamino, C₁₋₆alkyl sulfonamide, azido, —CHO, —CO₂H,            C₁₋₆alkyl carboxylate, cyano, C₂₋₆alkeny, and C₂₋₆alkynyl            group; and the C₁₋₆alkyl, cyclic —(C₁₋₈alkyl)-, cyclic            —(C₁₋₆oxaalkyl)-, cyclic —(C₁₋₆azaalkyl)-, C₂₋₆alkenyl, or            C₂₋₆alkynyl groups are selectively functionalized with one            or more halogen, thiol, hydroxyl, carbonyl, carboxyl,            carbonyloxyl, C₁₋₆alkoxy, C₁₋₆hydroxyalkoxy, amino,            C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, azido, piperidinyl,            phenyl, naphthyl, pyridyl, pyrimidinyl, imidazolyl,            1,2,3-triazolyl, quinolinyl, isoquinolinyl, thiazolyl, or            tetrazolyl groups

In another embodiment, Z is O or S, G is N, and R¹ is hydrogenC₁₋₆alkyl, or C₁₋₆alkyl selectively functionalized with one or morehalogen, thiol, hydroxyl, carbonyl, carboxyl, carbonyloxyl, C₁₋₆alkoxy,C₁₋₆hydroxyalkoxy, amino, C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, or azidogroups.

In another embodiment, G is N, Z is NR^(1a), and R¹-R^(1a) is connectedas a —CH₂CH₂—, —CH₂CH₂CH₂—, —CH═CH—, —C(CH₃)═CH—, or —CH═C(CH₃)— group.

In another embodiment, G is C, Z is NR^(1a), and R¹-R^(1a) is connectedas a ═CH—CH═CH—, ═N—CH═CH—, or ═CH—N═CH— group.

In another embodiment, G is N, R¹ is methyl, Z is O, R³ and R⁴ areindependently hydrogen or halogen, and R⁶ is —OR^(3a), —OCH₂R^(3b), or—OCH(CH₃)R^(3b); wherein

-   -   R^(3a) and R^(3b) are independently hydrogen, phenyl, naphthyl,        pyridyl, pyrimidinyl, imidazolyl, 1,2,3-triazolyl, quinolinyl,        isoquinolinyl, thiazolyl, tetrazolyl groups, C₁₋₆alkyl, cyclic        —(C₁₋₈alkyl)-, cyclic —(C₁₋₆oxaalkyl)-, cyclic —(C₁₋₆azaalkyl)-,        C₂₋₆alkenyl, C₂₋₆alkynyl;        -   wherein the phenyl, naphthyl, pyridyl, pyrimidinyl,            imidazolyl, 1,2,3-triazolyl, quinolinyl, isoquinolinyl,            thiazolyl, or tetrazolyl groups are optionally substituted            with 1-3 substituents independently selected from the group            consisting of halogen, thiol, C₁₋₆alkyl thioether, C₁₋₆alkyl            sulfoxide, C₁₋₆alkyl, C₁₋₆alkoxyl, amino, C₁₋₆alkylamino,            C₁₋₆dialkylamino, C₁₋₆alkyl sulfonamide, azido, —CHO, —CO₂H,            C₁₋₆alkyl carboxylate, cyano, C₂₋₆alkeny, and C₂₋₆alkynyl            group; and the C₁₋₆alkyl, cyclic —(C₁₋₈alkyl)-, cyclic            —(C₁₋₆oxaalkyl)-, cyclic —(C₁₋₆azaalkyl)-, C₂₋₆alkenyl, or            C₂₋₆alkynyl groups are selectively functionalized with one            or more halogen, thiol, hydroxyl, carbonyl, carboxyl,            carbonyloxyl, C₁₋₆alkoxy, C₁₋₆hydroxyalkoxy, amino,            C₁-6alkylamino, di(C₁₋₆alkyl)amino, azido, piperidinyl,            phenyl, naphthyl, pyridyl, pyrimidinyl, imidazolyl,            1,2,3-triazolyl, quinolinyl, isoquinolinyl, thiazolyl, or            tetrazolyl groups.

In another embodiment, the compound of Formula I comprising thestructure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I comprising thestructure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I comprising thestructure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I comprising thestructure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I comprising thestructure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I comprising thestructure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I comprising thestructure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I comprising thestructure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I comprising thestructure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I comprising thestructure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I comprising thestructure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I comprising thestructure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I comprising thestructure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I comprising thestructure:

or a pharmaceutically acceptable salt thereof.

In another embodimet, the compound of Formual I comprising thestructure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I comprising thestructure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I comprising thestructure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I comprising thestructure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I comprising thestructure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I comprising thestructure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I comprising thestructure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I comprising thestructure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I comprising thestructure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I comprising thestructure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I comprising thestructure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I comprising thestructure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I comprising thestructure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I comprising thestructure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I comprising thestructure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I comprising thestructure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I comprising thestructure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I comprising thestructure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I comprising thestructure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I comprising thestructure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I comprising thestructure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I comprising thestructure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I comprising thestructure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I comprising thestructure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I comprising thestructure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I comprising thestructure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I comprising thestructure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I comprising thestructure:

or a pharmaceutically salt thereof.

In another embodiment, the compound of Formula I comprising thestructure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I comprising thestructure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I comprising thestructure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I comprising thestructure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I comprising thestructure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I comprising thestructure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I comprising thestructure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I comprising thestructure:

or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, and one or more of pharmaceutically acceptableexcipients.

In another aspect, the present invention provides a compound of FormulaI, or a pharmaceutically acceptable salt thereof, for use in therapy.

In another aspect, the present invention provides a compound of FormulaI, or a pharmaceutically acceptable salt thereof, for use in thetreatment of a disease or condition in which modulation of cGAS activityis beneficial.

In another aspect, the present invention provides a compound of FormulaI, or a pharmaceutically acceptable salt thereof, for use in thetreatment of an inflammatory, allergic, autoimmune, or infectiousdisease.

In another aspect, the present invention provides a compound of FormulaI, or a pharmaceutically acceptable salt thereof, for use in thetreatment of a senescence- or age-related disease.

In another aspect, the present invention provides a method for treatinga disease or condition for which modulation of cGAS activity isbeneficial comprising: administering to a patient in need thereof, atherapeutically effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a method of treatingan inflammatory, allergic, autoimmune, or infectious disease comprising:administering to a patient in need thereof, a therapeutically effectiveamount of a compound of Formula I, or a pharmaceutically acceptable saltthereof.

In another aspect, the present invention provides a method of treating asenescence- or age-related disease comprising: administering to apatient in need thereof, a therapeutically effective amount of acompound of Formula I, or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides the use of a compoundof Formula I, or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for use the treatment of a disease orcondition for which modulation of cGAS is beneficial.

In another aspect, the present invention provides the use of a compoundof Formula I, or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for use the treatment of an inflammatory,allergic, autoimmune or infectious disease.

In another aspect, the present invention provides the use of a compoundof Formula I, or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for use the treatment of a senescence- orage-related disease.

In another aspect, the present invention provides pharmaceuticalcomposition comprising: a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, and at least one further therapeutic agent.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising: a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, at least one further therapeutic agent, and oneor more of pharmaceutically acceptable excipients.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising: a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, and at least one further therapeutic agent foruse in therapy.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising: a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, and at least one further therapeutic agent foruse in the treatment of a disease or condition for which modulation ofcGAS is beneficial.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising: a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, and at least one further therapeutic agent foruse in the treatment of an inflammatory, allergic, autoimmune, orinfectious diseases.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising: a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, and at least one further therapeutic agent foruse in the treatment of a senescence- or age-related disease.

In another aspect, the present invention provides a method for treatinga disease or condition for which modulation of cGAS is beneficialcomprising: administering to a patient in need thereof, atherapeutically effective amount of a combination comprising a compoundof Formula I, or a pharmaceutically acceptable salt thereof, and atleast one further therapeutic agent.

In another aspect, the present invention provides a method of treatingan inflammatory, allergic, autoimmune or infectious disease comprising:administering to a patient in need thereof, a therapeutically effectiveamount of a pharmaceutical composition comprising: a compound of FormulaI, or a pharmaceutically acceptable salt thereof, and at least onefurther therapeutic agent.

In another aspect, the present invention provides a method of treating asenescence- or age-related disease comprising: administering to apatient in need thereof, a therapeutically effective amount of apharmaceutical composition comprising: a compound of Formula I, or apharmaceutically acceptable salt thereof, and at least one furthertherapeutic agent.

While aspects for each variable have generally been listed aboveseparately for each variable this invention includes those compounds inwhich several or each aspect in formula I is selected from each of theaspects listed above. Therefore, this invention is intended to includeall combinations of aspects for each variable.

DETAILED DESCRIPTION OF THE INVENTION

As used herein:

The term “a compound of the invention” includes all solvates, complexes,polymorphs, radiolabeled derivatives, tautomers, stereoisomers, andoptical isomers of the compounds of Formula I, and salts thereof, unlessotherwise specified.

The term “effective amount” means that amount of a drug orpharmaceutical agent that will elicit the biological or medical responseof a tissue, system, animal or human that is being sought, for instance,by a researcher or clinician.

The term “therapeutically effective amount” means any amount which, ascompared to a corresponding subject who has not received such amount,results in improved treatment, healing, prevention, or amelioration of adisease, disorder, or side effect, or a decrease in the rate ofadvancement of a disease or disorder. The term also includes within itsscope amounts effective to enhance normal physiological function.

The term “prophylaxis” includes prevention and refers to a measure orprocedure which is to prevent rather than cure or treat a disease.Preventing refers to a reduction in risk of acquiring or developing adisease causing at least one clinical symptom of the disease not todeveloping a subject that may be exposed to a disease-causing agent or asubject predisposed to the disease in advance of disease outset.

The term “pharmaceutically acceptable” refers to those compounds,materials, compositions, and dosage forms which are, within the scope ofsound medical judgment, suitable for use in contact with the tissues ofhuman beings and animals without excessive toxicity, irritation, orother problem or complication, commensurate with a reasonablebenefit/risk ratio.

The term “pharmaceutically acceptable excipients” includes all diluents,carriers, binders, glidants, and other components of pharmaceuticalformulations with which the compound of the invention is administered.

The compounds of the invention may exist in solid or liquid form. Insolid form, compound of the invention may exist in a continuum of solidstates ranging from fully amorphous to fully crystalline.

The term ‘amorphous’ refers to a state in which the material lacks longrange order at the molecular level and, depending upon the temperature,may exhibit the physical properties of a solid or a liquid. Typically,such materials do not give distinctive X-ray diffraction patterns and,while exhibiting the properties of a solid, are more formally describedas a liquid. Upon heating, a change from solid to liquid propertiesoccurs which is characterized by a change of state, typically secondorder (‘glass transition’).

The term ‘crystalline’ refers to a solid phase in which the material hasa regular ordered internal structure at the molecular level and gives adistinctive X-ray diffraction pattern with defined peaks. Such materialswhen heated sufficiently will also exhibit the properties of a liquid,but the change from solid to liquid is characterized by a phase change,typically first order (‘melting point’).

The compounds of the invention may have the ability to crystallize inmore than one form, a characteristic, which is known as polymorphism,and it is understood that such polymorphic forms (“polymorphs”) arewithin the scope of the invention. Polymorphism generally can occur as aresponse to changes in temperature or pressure or both and can alsoresult from variations in the crystallization process. Polymorphs can bedistinguished by various physical characteristics known in the art suchas x-ray diffraction patterns, solubility and melting point.

The compound of Formula I may exist in solvated and unsolvated forms. Asused herein, the term “solvate” refers to a complex of variablestoichiometry formed by a solute (in this invention, a compound offormula I or a salt) and a solvent. Such solvents for the purpose of theinvention may not interfere with the biological activity of the solute.The skilled artisan will appreciate that pharmaceutically acceptablesolvates may be formed for crystalline compounds wherein solventmolecules are incorporated into the crystalline lattice duringcrystallization. The incorporated solvent molecules may be watermolecules or non-aqueous such as ethanol, isopropanol, DMSO, aceticacid, ethanolamine, and ethyl acetate molecules. Crystalline latticeincorporated with water molecules are typically referred to as“hydrates”. Hydrates include stoichiometric hydrates as well ascompositions containing variable amounts of water. The present inventionincludes all such solvates.

It is also noted that some compounds may form tautomers. ‘Tautomers’refer to compounds that are interchangeable forms of a particularcompound structure, and that vary in the displacement of hydrogen atomsand electrons. Thus, two structures may be in equilibrium through themovement of electrons and an atom (usually H). For example, enols andketones are tautomers because they are rapidly interconverted bytreatment with either acid or base. It is understood that all tautomersand mixtures of tautomers of the compounds of the present invention areincluded within the scope of the compounds of the present invention. Forabsolute clarity, in the compounds of formula I when R¹ or R³ representOH, the compounds will form the keto tautomer (═O).

The compounds of Formula I may be in the form of a salt. Typically, thesalts of the present invention are pharmaceutically acceptable salts.Salts encompassed within the term “pharmaceutically acceptable salts”refer to non-toxic salts of the compounds of this invention. For areview on suitable salts, see e.g., Berge et al, J. Pharm. Sci. 1977,66, 1-19. Suitable pharmaceutically acceptable salts can include acidaddition salts. A pharmaceutically acceptable acid addition salt can beformed by reaction of a compound of Formula I with a suitable inorganicor organic acid (such as hydrobromic, hydrochloric, sulfuric, nitric,phosphoric, p-toluenesulfonic, benzenesulfonic, methanesulfonic,ethanesulfonic, naphthalenesulfonic such as 2-naphthalenesulfonic),optionally in a suitable solvent such as an organic solvent, to give thesalt which is usually isolated for example by crystallisation andfiltration. A pharmaceutically acceptable acid addition salt of acompound of Formula I can be, for example, a hydrobromide,hydrochloride, sulfate, nitrate, phosphate, p-toluenesulfonate,benzenesulfonate, methanesulfonate, ethanesulfonate, ornaphthalenesulfonate (e.g. 2-naphthalenesulfonate) salt. Othernon-pharmaceutically acceptable salts, e.g. trifluoroacetates, may beused, for example in the isolation of compounds of the invention, andare included within the scope of this invention.

The invention includes within its scope all possible stoichiometric andnon-stoichiometric forms of the compounds of Formula I.

While it is possible that, for use in therapy, the compound of theinvention may be administered as the raw chemical, it is possible topresent the compound of the invention as the active ingredient in apharmaceutical composition. Such compositions can be prepared in amanner well known in the pharmaceutical art and comprise at least oneactive compound. Accordingly, the invention further providespharmaceutical compositions comprising a compound of the invention andone or more pharmaceutically acceptable excipients. The excipient(s)must be acceptable in the sense of being compatible with the otheringredients of the composition and not deleterious to the recipientthereof. In accordance with another aspect of the invention there isalso provided a process for the preparation of a pharmaceuticalcomposition including the agent, or pharmaceutically acceptable saltsthereof, with one or more pharmaceutically acceptable excipients. Thepharmaceutical composition can be for use in the treatment and/orprophylaxis of any of the conditions described herein.

Generally, the compound of the invention is administered in apharmaceutically effective amount. The amount of the compound actuallyadministered will typically be determined by a physician, in the lightof the relevant circumstances, including the condition to be treated,the chosen route of administration, the actual compound-administered,the age, weight, and response of the individual patient, the severity ofthe patient's symptoms, and the like. Pharmaceutical compositions may bepresented in unit dose forms containing a predetermined amount of activeingredient per unit dose. The term “unit dosage forms” refers tophysically discrete units suitable as unitary dosages for human subjectsand other mammals, each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient, vehicle orcarrier. Typical unit dosage forms include prefilled, premeasuredampules or syringes of the liquid compositions or pills, tablets,capsules or the like in the case of solid compositions.

Preferred unit dosage compositions are those containing a daily dose orsub-dose, or an appropriate fraction thereof, of an active ingredient.Such unit doses may therefore be administered once or more than once aday. Such pharmaceutical compositions may be prepared by any of themethods well known in the pharmacy art.

Pharmaceutical compositions may be adapted for administration by anyappropriate route, for example by the oral (including buccal orsublingual), rectal, inhaled, intranasal, topical (including buccal,sublingual or transdermal), vaginal or parenteral (includingsubcutaneous, intramuscular, intravenous or intradermal) route. Suchcompositions may be prepared by any method known in the art of pharmacy,for example by bringing into association the active ingredient with thecarrier(s) or excipient(s).

Pharmaceutical compositions adapted for oral administration may bepresented as discrete units such as capsules or tablets; powders orgranules; solutions or suspensions in aqueous or non-aqueous liquids;edible foams or whips; or oil-in-water liquid emulsions or water-in-oilliquid emulsions.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert excipient such as ethanol,glycerol, water and the like. Powders are prepared by reducing thecompound to a suitable fine size and mixing with a similarly preparedpharmaceutical excipient such as an edible carbohydrate, as, forexample, starch or mannitol. Flavoring, preservative, dispersing andcoloring agent can also be present.

Capsules are made by preparing a powder mixture, as described above, andfilling formed gelatin sheaths. Excipients including glidants andlubricants such as colloidal silica, talc, magnesium stearate, calciumstearate or solid polyethylene glycol can be added to the powder mixturebefore the filling operation. A disintegrating or solubilizing agentsuch as agar-agar, calcium carbonate or sodium carbonate can also beadded to improve the availability of the medicament when the capsule isingested.

Moreover, when desired or necessary, excipients including suitablebinders, glidants, lubricants, sweetening agents, flavors,disintegrating agents and coloring agents can also be incorporated intothe mixture. Suitable binders include starch, gelatin, natural sugarssuch as glucose or beta-lactose, corn sweeteners, natural and syntheticgums such as acacia, tragacanth or sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes and the like.Lubricants used in these dosage forms include sodium oleate, sodiumstearate. magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride and the like. Disintegrators include, without limitation,starch, methyl cellulose, agar, bentonite, xanthan gum and the like.Tablets are formulated, for example, by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally, with a binder such as carboxymethylcellulose, analiginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paraffin, a resorption accelerator such as a quaternary salt and/oran absorption agent such as bentonite, kaolin or dicalcium phosphate.The powder mixture can be granulated by wetting with a binder such assyrup, starch paste, acadia mucilage or solutions of cellulosic orpolymeric materials and forcing through a screen. As an alternative togranulating, the powder mixture can be run through the tablet machineand the result is imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc ormineral oil. The lubricated mixture is then compressed into tablets. Thecompounds of the present invention can also be combined with a freeflowing inert carrier and compressed into tablets directly without goingthrough the granulating or slugging steps. A clear or opaque protectivecoating consisting of a sealing coat of shellac, a coating of sugar orpolymeric material and a polish coating of wax can be provided.Dyestuffs can be added to these coatings to distinguish different unitdosages.

Oral fluids such as solution, suspensions, syrups and elixirs can beprepared in dosage unit form so that a given quantity contains apredetermined amount of the compound. Syrups can be prepared bydissolving the compound in a suitably flavoured aqueous solution, whileelixirs are prepared through the use of a non-toxic alcoholic vehicle.Suspensions can be formulated by dispersing the compound in a non-toxicvehicle. Solubilizers and emulsifiers such as ethoxylated isostearylalcohols and polyoxy ethylene sorbitol ethers, preservatives, flavoradditive such as peppermint oil or natural sweeteners or saccharin orother artificial sweeteners, and the like can also be added.

Where appropriate, dosage unit compositions for oral administration canbe microencapsulated. The composition can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax or the like.

The compounds of the invention may also be administered in the form ofliposome delivery systems, such as small unilamellar vesicles, largeunilamellar vesicles and multilamellar vesicles. Liposomes can be formedfrom a variety of phospholipids, such as cholesterol, stearylamine orphosphatidylcholines. Pharmaceutical compositions adapted fortransdermal administration may be presented as discrete patches intendedto remain in intimate contact with the epidermis of the recipient for aprolonged period of time.

Pharmaceutical compositions adapted for topical administration may beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils.

For treatments of the eye or other external tissues, for example mouthand skin, the compositions are preferably applied as a topical ointmentor cream. When formulated in an ointment, the active ingredient may beemployed with either a paraffinic or a water-miscible ointment base.Alternatively, the active ingredient may be formulated in a cream withan oil-in-water cream base or a water-in-oil base.

Pharmaceutical compositions adapted for topical administrations to theeye include eye drops wherein the active ingredient is dissolved orsuspended in a suitable carrier, especially an aqueous solvent.

Pharmaceutical compositions adapted for topical administration in themouth include lozenges, pastilles and mouth washes.

Pharmaceutical compositions adapted for rectal administration may bepresented as suppositories or as enemas.

Dosage forms for nasal or inhaled administration may conveniently beformulated as aerosols, solutions, suspension drops, gels or drypowders.

Compositions for intranasal administration include aqueous compositionsadministered to the nose by drops or by pressurised pump. Suitablecompositions contain water as the diluent or carrier for this purpose.Compositions for administration to the lung or nose may contain one ormore excipients, for example one or more suspending agents, one or morepreservatives, one or more surfactants, one or more tonicity adjustingagents, one or more co-solvents, and may include components to controlthe pH of the composition, for example a buffer system. Further, thecompositions may contain other excipients such as antioxidants, forexample sodium metabisulphite, and taste-masking agents. Compositionsmay also be administered to the nose or other regions of the respiratorytract by nebulisation. Intranasal compositions may permit thecompound(s) of Formula I or (a) pharmaceutically acceptable salt(s)thereof to be delivered to all areas of the nasal cavities (the targettissue) and further, may permit the compound(s) of Formula I or (a)pharmaceutically acceptable salt(s) thereof to remain in contact withthe target tissue for longer periods of time. A suitable dosing regimefor intranasal compositions would be for the patient to inhale slowlythrough the nose subsequent to the nasal cavity being cleared. Duringinhalation, the composition would be administered to one nostril whilethe other is manually compressed. This procedure would then be repeatedfor the other nostril. Typically, one or two sprays per nostril would beadministered by the above procedure one, two, or three times each day,ideally once daily. Of particular interest are intranasal compositionssuitable for once-daily administration.

The suspending agent(s), if included, will typically be present in anamount of from 0.1 to 5% (w/w), such as from 1.5% to 2.4% (w/w), basedon the total weight of the composition. Examples of pharmaceuticallyacceptable suspending agents include, but are not limited to, Avicef(microcrystalline cellulose and carboxymethylcellulose sodium),carboxymethylcellulose sodium, veegum, tragacanth, bentonite,methylcellulose, xantha n gum, carbopol and polyethylene glycols.

Compositions for administration to the lung or nose may contain one ormore excipients may be protected from microbial or fungal contaminationand growth by inclusion of one or more preservatives. Examples ofpharmaceutically acceptable anti-microbial agents or preservativesinclude, but are not limited to, quaternary ammonium compounds (forexample benzalkonium chloride, benzethonium chloride, cetrimide,cetylpyridinium chloride, lauralkonium chloride and myristyl picoliniumchloride), mercurial agents (for example phenylmercuric nitrate,phenylmercuric acetate and thimerosal), alcoholic agents (for examplechlorobutanol, phenylethyl alcohol and benzyl alcohol), antibacterialesters (for example esters ofp-hydroxybenzoic acid), chelating agentssuch as disodium edetate (EDTA) and other anti-microbial agents such aschlorhexidine, chlorocresol, sorbic acid and its salts (such aspotassium sorbate) and polymyxin. Examples of pharmaceuticallyacceptable anti-fungal agents or preservatives include, but are notlimited to, sodium benzoate, sorbic acid, sodium propionate,methylparaben, ethylparaben, propylparaben and butylparaben. Thepreservative(s), if included, may be present in an amount of from 0.001to 1% (w/w), such as from 0.015% to 0.5% (w/w) based on the total weightof the composition. Compositions (for example wherein at least onecompound is in suspension) may include one or more surfactants whichfunctions to facilitate dissolution of the medicament particles in theaqueous phase of the composition. For example, the amount of surfactantused is an amount which will not cause foaming during mixing. Examplesof pharmaceutically acceptable surfactants include fatty alcohols,esters and ethers, such as polyoxyethylene (20) sorbitan monooleate(Polysorbate 80), macrogol ethers, and poloxamers. The surfactant may bepresent in an amount of between about 0.01 to 10% (w/w), such as from0.01 to 0.75% (w/w), for example about 0.5% (w/w), based on the totalweight of the composition.

One or more tonicity-adjusting agent(s) may be included to achievetonicity with body fluids e.g. fluids of the nasal cavity, resulting inreduced levels of irritancy. Examples of pharmaceutically acceptabletonicity-adjusting agents include, but are not limited to, sodiumchloride, dextrose, xylitol, calcium chloride, glucose, glycerine andsorbitol. A tonicity-adjusting agent, if present, may be included in anamount of from 0.1 to 10% (w/w), such as from 4.5 to 5.5% (w/w), forexample about 5.0% (w/w), based on the total weight of the composition.

The compositions of the invention may be buffered by the addition ofsuitable buffering agents such as sodium citrate, citric acid,trometamol, phosphates such as disodium phosphate (for example thedodecahydrate, heptahydrate, dihydrate and anhydrous forms), or sodiumphosphate and mixtures thereof.

A buffering agent, if present, may be included in an amount of from 0.1to 5% (w/w), for example 1 to 3% (w/w) based on the total weight of thecomposition.

Examples of taste-masking agents include sucralose, sucrose, saccharinor a salt thereof, fructose, dextrose, glycerol, corn syrup, aspartame,acesulfame-K, xylitol, sorbitol, erythritol, ammonium glycyrrhizinate,thaumatin, neotame, mannitol, menthol, eucalyptus oil, camphor, anatural flavouring agent, an artificial flavouring agent, andcombinations thereof.

One or more co-solvent(s) may be included to aid solubility of themedicament compound(s) and/or other excipients. Examples ofpharmaceutically acceptable co-solvents include, but are not limited to,propylene glycol, dipropylene glycol, ethylene glycol, glycerol,ethanol, polyethylene glycols (for example PEG300 or PEG400), andmethanol. In one embodiment, the co-solvent is propylene glycol.

Co-solvent(s), if present, may be included in an amount of from 0.05 to30% (w/w), such as from 1 to 25% (w/w), for example from 1 to 10% (w/w)based on the total weight of the composition.

Compositions for inhaled administration include aqueous, organic oraqueous/organic mixtures, dry powder or crystalline compositionsadministered to the respiratory tract by pressurised pump or inhaler,for example, reservoir dry powder inhalers, unit-dose dry powderinhalers, pre-metered multi-dose dry powder inhalers, nasal inhalers orpressurised aerosol inhalers, nebulisers or insufflators. Suitablecompositions contain water as the diluent or carrier for this purposeand may be provided with conventional excipients such as bufferingagents, tonicity modifying agents and the like. Aqueous compositions mayalso be administered to the nose and other regions of the respiratorytract by nebulisation. Such compositions may be aqueous solutions orsuspensions or aerosols delivered from pressurised packs, such as ametered dose inhaler, with the use of a suitable liquefied propellant.

Compositions for administration topically to the nose (for example, forthe treatment of rhinitis) or to the lung, include pressurised aerosolcompositions and aqueous compositions delivered to the nasal cavities bypressurised pump. Compositions which are non-pressurised and aresuitable for administration topically to the nasal cavity are ofparticular interest. Suitable compositions contain water as the diluentor carrier for this purpose. Aqueous compositions for administration tothe lung or nose may be provided with conventional excipients such asbuffering agents, tonicity-modifying agents and the like. Aqueouscompositions may also be administered to the nose by nebulisation.

A fluid dispenser may typically be used to deliver a fluid compositionto the nasal cavities. The fluid composition may be aqueous ornon-aqueous, but typically aqueous. Such a fluid dispenser may have adispensing nozzle or dispensing orifice through which a metered dose ofthe fluid composition is dispensed upon the application of auser-applied force to a pump mechanism of the fluid dispenser. Suchfluid dispensers are generally provided with a reservoir of multiplemetered doses of the fluid composition, the doses being dispensable uponsequential pump actuations. The dispensing nozzle or orifice may beconfigured for insertion into the nostrils of the user for spraydispensing of the fluid composition into the nasal cavity.

Dry powder compositions for topical delivery to the lung by inhalationmay, for example, be presented in capsules and cartridges of for examplegelatine, or blisters of for example laminated aluminium foil, for usein an inhaler or insufflator. Powder blend compositions generallycontain a powder mix for inhalation of the compound of formula I or apharmaceutically acceptable salt thereof and a suitable powder base(carrier/diluent/excipient substance) such as mono-, di-, orpolysaccharides (for example lactose or starch). Dry powder compositionsmay also include, in addition to the drug and carrier, a furtherexcipient (for example a ternary agent such as a sugar ester for examplecellobiose octaacetate, calcium stearate, or magnesium stearate.

Pharmaceutical compositions adapted for parental administration includeaqueous and nonaqueous sterile injection solutions which may containanti-oxidants, buffers, bacteriostats and solutes which render thecomposition isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The compositions may be presented inunit-dose or multi-dose containers, for example sealed ampoules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use. Extemporaneous injectionsolutions and suspensions may be prepared from sterile powders, granulesand tablets.

It should be understood that in addition to the ingredients particularlymentioned above, the compositions may include other agents conventionalin the art having regard to the type of formulation in question, forexample, those suitable for oral administration may include flavouringagents.

A therapeutically effective amount of the agent will depend upon anumber of factors including, for example, the age and weight of thesubject, the precise condition requiring treatment and its severity, thenature of the formulation, and the route of administration, and willultimately be at the discretion of the attendant physician orveterinarian. In particular, the subject to be treated is a mammal,particularly a human.

The agent may be administered in a daily dose. This amount may be givenin a single dose per day or more usually in a number (such as two,three, four, five or six) of sub-doses per day such that the total dailydose is the same.

Suitably, the amount of the compound of the invention administeredaccording to the present invention will be an amount selected from 0.01mg to 10 g per day (calculated as the free or unsalted compound).

The compounds of Formula I and pharmaceutically acceptable salts thereofmay be employed alone or in combination with other therapeutic agents.The compounds of Formula I and pharmaceutically acceptable salts thereofand the other pharmaceutically active agent(s) may be administeredtogether or separately and, when administered separately, administrationmay occur simultaneously or sequentially, in any order, by anyconvenient route in separate or combined pharmaceutical compositions.The amounts of the compound(s) of Formula I or pharmaceuticallyacceptable salt(s) thereof and the other pharmaceutically activeagent(s) and the relative timings of administration will be selected inorder to achieve the desired combined therapeutic effect. Thecompound(s) of Formula I or pharmaceutically acceptable salt(s) thereofand further therapeutic agent(s) may be employed in combination byadministration simultaneously in a unitary pharmaceutical compositionincluding both compounds. Alternatively, the combination may beadministered separately in separate pharmaceutical compositions, eachincluding one of the compounds in a sequential manner wherein, forexample, the compound of the invention is administered first and theother second and visa versa. Such sequential administration may be closein time (e.g. simultaneously) or remote in time. Furthermore, it doesnot matter if the compounds are administered in the same dosage form,e.g. one compound may be administered topically and the other compoundmay be administered orally. Suitably, both compounds are administeredorally.

The combinations may be presented as a combination kit. By the term“combination kit” “or kit of parts” as used herein is meant thepharmaceutical composition or compositions that are used to administerthe combination according to the invention. When both compounds areadministered simultaneously, the combination kit can contain bothcompounds in a single pharmaceutical composition, such as a tablet, orin separate pharmaceutical compositions. When the compounds are notadministered simultaneously, the combination kit will contain eachcompound in separate pharmaceutical compositions either in a singlepackage or in separate pharmaceutical compositions in separate packages.The combination kit can also be provided by instruction, such as dosageand administration instructions. Such dosage and administrationinstructions can be of the kind that are provided to a doctor, forexample by a drug product label, or they can be of the kind that areprovided by a doctor, such as instructions to a patient.

When the combination is administered separately in a sequential mannerwherein one is administered first and the other second or vice versa,such sequential administration may be close in time or remote in time.For example, administration of the other agent several minutes toseveral dozen minutes after the administration of the first agent, andadministration of the other agent several hours to several days afterthe administration of the first agent are included, wherein the lapse oftime is not limited. For example, one agent may be administered once aday, and the other agent may be administered 2 or 3 times a day, or oneagent may be administered once a week, and the other agent may beadministered once a day and the like. It will be clear to a personskilled in the art that, where appropriate, the other therapeuticingredients(s) may be used in the form of salts, for example as alkalimetal or amine salts or as acid addition salts, or prodrugs, or asesters, for example lower alkyl esters, or as solvates, for examplehydrates, to optimize the activity and/or stability and/or physicalcharacteristics, such as solubility, of the therapeutic ingredient. Itwill be clear also that, where appropriate, the therapeutic ingredientsmay be used in optically pure form.

When combined in the same composition it will be appreciated that thetwo compounds must be stable and compatible with each other and theother components of the composition and may be formulated foradministration. When formulated separately they may be provided in anyconvenient composition, conveniently, in such a manner as known for suchcompounds in the art.

When the compound of Formula I is used in combination with a secondtherapeutic agent active against the same disease, condition ordisorder, the dose of each compound may differ from that when thecompound is used alone. Appropriate doses will be readily appreciated bythose skilled in the art.

In one embodiment, the mammal in the methods and uses of the presentinvention is a human. The compounds of the invention are useful in thetreatment of diseases and conditions in which modulation of cGAS isbeneficial. As modulators of the immune response, the compounds ofFormula I and pharmaceutically acceptable salts thereof may also beuseful, as stand-alone, in combination or as adjuvants, in the treatmentof diseases and conditions in which modulation of cGAS is beneficial.

In one aspect, the disease or condition is an inflammatory, allergic orautoimmune diseases such as systemic lupus erythematosus, psoriasis,insulin-dependent diabetes mellitus (IDDM), scleroderma, AicardiGourtiers syndrome, dermatomyositis, inflammatory bowel diseases,multiple sclerosis, rheumatoid arthritis and Sjogren's syndrome (SS).

In another aspect, the disease or condition is an infectious diseasesuch as bacterial, viral or parasitic disease in which modulation ofcGAS activity is beneficial.

In another aspect, the disease or condition is a senescence- orage-related disease, including a neurodegenerative disease such asAlzheimer's or Parkinson disease, cardiovascular diseases such asatherosclerosis or myocardial infaction, liver or renal diseases, canceror premature aging.

Inflammation represents a group of vascular, cellular, and neurologicalresponses to trauma. Inflammation can be characterized as the movementof inflammatory cells such as monocytes, neutrophils and granulocytesinto the tissues. This is usually associated with reduced endothelialbarrier function and edema into the tissues. Inflammation can beclassified as either acute or chronic. Acute inflammation is the initialresponse of the body to harmful stimuli and is achieved by the increasedmovement of plasma and leukocytes from the blood into the injuredtissues. A cascade of biochemical event propagates and matures theinflammatory response, involving the local vascular system, the immunesystem, and various cells within the injured tissue. Prolongedinflammation, known as chronic inflammation, leads to a progressiveshift in the type of cells which are present at the site of inflammationand is characterized by simultaneous destruction and healing of thetissue from the inflammatory process.

When occurring as part of an immune response to infection or as an acuteresponse to trauma, inflammation can be beneficial and is normallyself-limiting. However, inflammation can be detrimental under variousconditions. This includes the production of excessive inflammation inresponse to infectious agents, which can lead to significant organdamage and death (for example, in the setting of sepsis). Moreover,chronic inflammation is generally deleterious and is at the root ofnumerous chronic diseases, causing severe and irreversible damage totissues. In such settings, the immune response is often directed againstself-tissues (autoimmunity), although chronic responses to foreignentities can also lead to bystander damage to self-tissues. The aim ofanti-inflammatory therapy is therefore to reduce this inflammation, toinhibit autoimmunity when present and to allow for the physiologicalprocess or healing and tissue repair to progress.

The compounds of the invention may be used to treat inflammation of anytissue and organs of the body, including musculoskeletal inflammation,vascular inflammation, neural inflammation, digestive systeminflammation, ocular inflammation, inflammation of the reproductivesystem, and other inflammation, as exemplified below.

Musculoskeletal inflammation refers to any inflammatory condition of themusculoskeletal system, particularly those conditions affecting skeletaljoints, including joints of the hand, wrist, elbow, shoulder, jaw,spine, neck, hip, knew, ankle, and foot, and conditions affectingtissues connecting muscles to bones such as tendons. Examples ofmusculoskeletal inflammation which may be treated with compounds of theinvention include arthritis (including, for example, osteoarthritis,rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, acuteand chronic infectious arthritis, arthritis associated with gout andpseudogout, and juvenile idiopathic arthritis), tendonitis, synovitis,tenosynovitis, bursitis, fibrositis (fibromyalgia), epicondylitis,myositis, and osteitis (including, for example, Paget's disease,osteitis pubis, and osteitis fibrosa cystic). Ocular inflammation refersto inflammation of any structure of the eye, including the eye lids.Examples of ocular inflammation which may be treated with the compoundsof the invention include blepharitis, blepharochalasis, conjunctivitis,dacryoadenitis, keratitis, keratoconjunctivitis sicca (dry eye),scleritis, trichiasis, and uveitis. Examples of inflammation of thenervous system which may be treated with the compounds of the inventioninclude encephalitis, Guillain-Barre syndrome, meningitis,neuromyotonia, narcolepsy, multiple sclerosis, myelitis andschizophrenia.

Examples of inflammation of the vasculature or lymphatic system whichmay be treated with the compounds of the invention includearthrosclerosis, arthritis, phlebitis, vasculitis, and lymphangitis.

Examples of inflammatory conditions of the digestive system which may betreated with the compounds of the invention include cholangitis,cholecystitis, enteritis, enterocolitis. gastritis, gastroenteritis,inflammatory bowel disease (such as Crohn's disease and ulcerativecolitis), ileitis, and proctitis.

Examples of inflammatory conditions of the reproductive system which maybe treated with the compounds of the invention include cervicitis,chorioamnionitis, endometritis, epididymitis, omphalitis, oophoritis,orchitis, salpingitis, tubo-ovarian abscess, urethritis, vaginitis,vulvitis, and vulvodynia.

The agents may be used to treat autoimmune conditions having aninflammatory component. Such conditions include systemic lupuserythematosus, acute disseminated alopecia universalise, Behcet'sdisease, Chagas' disease, chronic fatigue syndrome, dysautonomia,encephalomyelitis, ankylosing spondylitis, aplastic anemia, hidradenitissuppurativa, autoimmune hepatitis, autoimmune oophoritis, celiacdisease, Crohn's disease, diabetes mellitus type 1, giant cellarteritis, goodpasture's syndrome. Grave's disease, Guillain-Barresyndrome, Hashimoto's disease, Henoch-Schonlein purpura, Kawasaki'sdisease, microscopic colitis, microscopic polyarteritis, mixedconnective tissue disease, multiple sclerosis, myasthenia gravis,opsoclonus myoclonus syndrome, optic neuritis, ord's thyroiditis,pemphigus, polyarteritis nodosa, polymyalgia, rheumatoid arthritis,Reiter's syndrome, Sjogren's syndrome, Aicardi Gourtiers syndrome,temporal arteritis, Wegener's granulomatosis, warm autoimmune haemolyticanemia, interstitial cystitis, lyme disease, morphea, psoriasis,sarcoidosis, scleroderma, ulcerative colitis, and vitiligo.

The compounds of the invention may be used to treat T-cell mediatedhypersensitivity diseases having an inflammatory component. Suchconditions include contact hypersensitivity, contact dermatitis(including that due to poison ivy), uticaria, skin allergies,respiratory allergies (hayfever, allergic rhinitis) and gluten-sensitiveenteropathy (Celliac disease).

Other inflammatory conditions which may be treated with the agentsinclude, for example, appendicitis, dermatitis, dermatomyositis,endocarditis, fibrositis, gingivitis, glossitis, hepatitis, hidradenitissuppurativa, iritis, laryngitis, mastitis, myocarditis, nephritis,otitis, pancreatitis, parotitis, percarditis, peritonoitis, pharyngitis,pleuritis, pneumonitis, prostatistis, pyelonephritis, and stomatisi,transplant rejection (involving organs such as kidney, liver, heart,lung, pancreas (e.g., islet cells), bone marrow, cornea, small bowel,skin allografts, skin homografts, and heart valve xengrafts, sewrumsickness, and graft vs host disease), acute pancreatitis, chronicpancreatitis, acute respiratory distress syndrome. Sexary's syndrome,congenital adrenal hyperplasis, nonsuppurative thyroiditis,hypercalcemia associated with cancer, pemphigus, bullous dermatitisherpetiformis, severe erythema multiforme, exfoliative dermatitis,seborrheic dermatitis, seasonal or perennial allergic rhinitis,bronchial asthma, contact dermatitis, astopic dermatitis, drughypersensistivity reactions, allergic conjunctivitis, keratitis, herpeszoster ophthalmicus, iritis and oiridocyclitis, chorioretinitis, opticneuritis, symptomatic sarcoidosis, fulminating or disseminated pulmonarytuberculosis chemotherapy, idiopathic thrombocytopenic purpura inadults, secondary thrombocytopenia in adults, acquired (autroimmine)haemolytic anemia, leukaemia and lymphomas in adults, acute leukaemia ofchildhood, regional enteritis, autoimmune vasculitis, multiplesclerosis, chronic obstructive pulmonary disease, solid organ transplantrejection, sepsis. Preferred treatments include treatment of transplantrejection, rheumatoid arthritis, psoriatic arthritis, multiplesclerosis. Type 1 diabetes, asthma, inflammatory bowel disease, systemiclupus erythematosis, psoriasis, chronic pulmonary disease, andinflammation accompanying infectious conditions (e.g., sepsis).

In a further aspect, the invention provides a compound of Formula I or apharmaceutically acceptable salt thereof for use in the treatment of aninflammatory, allergic or autoimmune disease.

In a further aspect, the invention provides a method of treating aninflammatory, allergic or autoimmune disease comprising: administeringto a patient in need thereof a therapeutically effective amount of acompound of Formula I or a pharmaceutically acceptable salt thereof.

In a further aspect, the invention provides the use of a compound ofFormula I or a pharmaceutically acceptable salt thereof in themanufacture of a medicament for the treatment of an inflammatory,allergic or autoimmune disease.

The Compounds of Formula I and pharmaceutically acceptable salts thereofmay be used in combination with one or more other agents in theprevention or treatment of an allergic inflammatory autoimmune disease,wherein such other agents can include: antigen immunotherapy agents;anti-histamines; steroids, NSAIDs; bronchodilators (e.g. beta 2agonists, adrenergic agonists, anticholinergic agents, theophylline);methotrexate; leukotriene modulators; monoclonal antibody agents such asanti-lgE, anti-TNF, anti-IL-5, anti-IL-6, anti-IL-12, anti-IL-1 andsimilar agents; receptor therapies agents such as entanercept; andantigen non-specific immunotherapeutic agents such interferon or othercytokines/chemokines, cytokine/chemokine receptor modulators, cytokineagonists or antagonists, and TLR antagonist.

In a further aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, and at least one further therapeutic agentuseful in the treatment of an allergic, inflammatory, or autoimmunedisease.

In a further aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, and at least one further therapeutic agentuseful in the treatment of an allergic, inflammatory or autoimmunedisease for use in therapy.

In a further aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of Formula I, or pharmaceuticallyacceptable salt thereof, and at least one further therapeutic agentuseful in the treatment of an allergic inflammatory or autoimmunedisease, for use in the treatment of allergic, inflammatory orautoimmune disease.

In a further aspect, the present invention provides the use of apharmaceutical composition comprising a compound of Formula I, or apharmaceutically acceptable salt thereof, and at least one furthertherapeutic agent useful in the treatment of an allergic, inflammatoryor autoimmune disease in the manufacture of a medicament for thetreatment of an allergic, inflammatory or autoimmune disease.

In a further aspect, the present invention provides a method of treatingan allergic, inflammatory or autoimmune disease comprising:administering to a patient in need thereof a therapeutically effectiveamount of a pharmaceutical composition comprising a compound of FormulaI, or a pharmaceutically acceptable salt thereof, and at least onefurther therapeutic agent useful in the treatment of an allergic,inflammatory, or autoimmune disease.

In a further aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, at least one further therapeutic agent usefulin the treatment of an allergic, inflammatory or autoimmune disease, andone or more of pharmaceutically acceptable excipients.

In a further aspect, the present invention provides a compound ofFormula I, or a pharmaceutically acceptable salt thereof, for use in thetreatment of an infectious disease.

In a further aspect, the present invention provides a method of treatingan infectious disease comprising administering to a patient in needthereof a therapeutically effective amount of a compound of Formula I,or a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides the use of acompound of Formula I, or a pharmaceutically acceptable salt thereof, inthe manufacture of a medicament for the treatment of an infectiousdisease. In one embodiment, the compound of the invention may beemployed with other therapeutic methods of treating infectious disease.In particular, bacterial and parasite infections, such as Mycobacteriumtuberculosis and malaria, respectively, which exploit the type-Iinterferon pathway for their advantage, may be treated with a cGASinhibitor.

The compounds of Formula I, and pharmaceutically acceptable saltsthereof, may be used in combination with one or more agents useful inthe prevention or treatment of bacterial and viral infections. Examplesof such agents include: polymerase inhibitors; replication inhibitorssuch as acyclovir, famciclovir, ganciclovir, cidofovir and lamivudine;protease inhibitors such as the HIV protease inhibitors saquinavir,ritonavir, indinavir, nelfinavir, amprenavir, fosamprenavir, brecanavir,atazanavir, tipranavir, palinavir, lasinavir, and the HCV proteaseinhibitors BILN2061, VX-950, SCH503034; nucleoside and nucleotidereverse transcriptase inhibitors such as zidovudine, didanosine,lamivudine, zalcitabine, abacavir, stavidine, adefovir, adefovirdipivoxil, fozivudine, todoxil, emtricitabine, alovudine, amdoxovir, andelvucitabine; non-nucleoside reverse transcriptase inhibitors (includingan agent having anti-oxidation activity such as immunocal or oltipraz)such as nevirapine, delavirdine, efavirenz, loviride, immunocal,oltipraz, capravirine, TMC-278, TMC-125, and etravirine; entryinhibitors such as enfuvirtide (T-20), T-1249, PRO-542, PRO-140,TNX-355, BMS-806, 5-Helix and similar agents; integrase inhibitors suchas L-870 and 180; budding inhibitors such as PA-344 and PA-457;chemokine receptor inhibitors such as vicriviroc (Sch-C), Sch-D, TAK779,maraviroc (UK-427,857), and TAK449; neuraminidase inhibitors such asCS-8958, zanamivir, oseltamivir, and peramivir; ion channel blockerssuch as amantadine or rimantadine; interfering RNA and antisenseoligonucleotides and such as ISIS-14803; and antiviral agents ofundetermined mechanism of action, such as ribavirin.

The compounds of Formula I and pharmaceutically acceptable saltsthereof, may also be used in combination with one or more other agentswhich may be useful in the prevention or treatment of viral infectionssuch as immune therapies (e.g. interferon or other cytokines/chemokines,cytokine/chemokine receptor modulators, cytokine agonists or antagonistsand similar agents); therapeutic vaccines; antifibrotic agents; andanti-inflammatory agents such as corticosteroids or NSAIDs(non-steroidal anti-inflammatory agents).

In a further aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, and at least one further therapeutic agentuseful in the treatment of an infectious disease.

In a further aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, and at least one further therapeutic agentuseful in the treatment of an infectious disease for use in therapy.

In a further aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of Formula I, or pharmaceuticallyacceptable salt thereof, and at least one further therapeutic agentuseful in the treatment of an infectious disease, for use in thetreatment of an infectious disease.

In a further aspect, the present invention provides the use of apharmaceutical composition comprising a compound of Formula I, or apharmaceutically acceptable salt thereof, and at least one furthertherapeutic agent useful in the treatment of an infectious disease inthe manufacture of a medicament for the treatment of an infectiousdisease.

In a further aspect, the present invention provides a method of treatingan infectious disease comprising administering to a patient in needthereof, a therapeutically effective amount of a pharmaceuticalcomposition comprising a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, and at least one further therapeutic agentuseful in the treatment of an infectious disease.

In a further aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of Formula I or a pharmaceuticallyacceptable salt thereof, at least one further therapeutic agent usefulin the treatment of infectious disease, and one or more ofpharmaceutically acceptable excipients.

In another aspect, the invention provides a compound of Formula I or apharmaceutically acceptable salt thereof for use in the treatment of asenescence- or age-related disease.

In a further aspect, the invention provides a method of treating asenescence- or age-related disease comprising: administering to apatient in need thereof a therapeutically effective amount of a compoundof Formula I or a pharmaceutically acceptable salt thereof.

In a further aspect, the invention provides the use of a compound ofFormula I or a pharmaceutically acceptable salt thereof in themanufacture of a medicament for the treatment of a senescence- orage-related disease.

In a further aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, and at least one further therapeutic agentuseful in the treatment of a senescence- or age-related disease.

In a further aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, and at least one further therapeutic agentuseful in the treatment of a senescence- or age-related disease for usein therapy.

In a further aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of Formula I, or pharmaceuticallyacceptable salt thereof, and at least one further therapeutic agentuseful in the treatment of a senescence- or age-related disease, for usein the treatment of a senescence- or age-related disease.

In a further aspect, the present invention provides the use of apharmaceutical composition comprising a compound of Formula I, or apharmaceutically acceptable salt thereof, and at least one furthertherapeutic agent useful in the treatment of a senescence- orage-related disease in the manufacture of a medicament for the treatmentof a senescence- or age-related disease.

In a further aspect, the present invention provides a method of treatinga senescence- or age-related disease comprising administering to apatient in need thereof, a therapeutically effective amount of apharmaceutical composition comprising a compound of Formula I, or apharmaceutically acceptable salt thereof, and at least one furthertherapeutic agent useful in the treatment of a senescence- orage-related disease.

In a further aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of Formula I or a pharmaceuticallyacceptable salt thereof, at least one further therapeutic agent usefulin the treatment of a senescence- or age-related disease, and one ormore of pharmaceutically acceptable excipients.

Compounds of Formula I may be prepared by methods known in the art oforganic synthesis as set forth in the schemes below and/or the specificExamples described below. In all of the methods, it is well understoodthat protecting groups for sensitive or reactive groups may be employedwhere necessary in accordance with general principles of chemistry.Protecting groups are manipulated according to standard methods oforganic synthesis (T. W. Green and P. G. M. Wuts (1999) ProtectiveGroups in Organic Synthesis, 3^(rd) edition, John Wiley & Sons). Thesegroups are removed at a convenient stage of the compound synthesis usingmethods that are readily apparent to those skilled in the art. Theselection of processes as well as the reaction conditions and order oftheir execution shall be consistent with the preparation of compounds ofFormula I.

The following list provides definitions of certain abbreviations as usedherein. It will be appreciated that the list is not exhaustive, but themeaning of those abbreviations not herein below defined will be readilyapparent to those skilled in the art: AIBN is2,2′-azobisisobutyronitrile; ATP is adenosine 5′-triphosphate; BPO isbenzoyl peroxide; n-BuLi is n-butyllithium; BzCl is benzoyl chloride;CDI is 1,1′-carbonyldiimidazole; cGAS is cyclic GMP-AMP synthase; CO iscarbon monooxide; Cu(OAc)₂ is copper(II) acetate; CuCN is copper(I)cynide; CuI is copper(I) iodide; DAST is (diethylamino)sulfurtrifluoride; DBU is 1,8-diazabicyclo[5.4.0]undec-7-ene; DCE isdichloroethane; DCM is dichloromethane; DDQ is2,3-dichloro-5,6-dicyano-p-benzoquinone; DHP is 3,4-dihydro-2H-pyran;DIAD is diisopropyl azodicarboxylate; DIBAL-H is diisobutylaluminumhydride; DIPA is diisopropylamine; DIPEA is N,N-diisopropylethylamine;DMAP is 4-(dimethylamino)pyridine; DMB is 2,4-dimethoxybenzyl; DMF isN,N-dimethylformamide; DMP is Dess-Martin periodinane; DMSO is dimethylsulfoxide; EA is ethyl acetate; EtMgBr is ethylmagnesium bromide; Et₂Ois diethyl ether; EtOH is ethanol; GTP is guanosine triphosphate; HCl ishydrochloric acid; HMTA is hexamethylenetetramine; HOAc is acetic acid;HPLC is high performance liquid chromatography; LAH is lithium aluminumhydride; mCPBA is 3-chloroperbenzoic acid; MeCN is acetonitrile; MeI isiodomethane; MeOH is methanol; MeMgBr is methylmagnesium bromide; MOMClis chloromethyl methyl ether; MOM is methoxymethoxy; MS is massspectrometer or mass spectrum; MsCl is methanesulfonyl chloride; MTBE ismethyl tert-butyl ether; NaH is sodium hydride; NaOH is sodiumhydroxide; NBS is N-bromosuccinimide; NMM is N-methylmorpholine; NMR isnuclear magnetic resonance; Pd(dba)₂ isbis(dibenzylideneacetone)palladium(0); Pd(dppf)Cl₂ is[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II); Pd(OAc)₂ ispalladium(II) acetate; Pd(PPh₃)₂Cl₂ isbis(triphenylphosphine)palladium(II) dichloride; Pd(PPh₃)₄ istetrakis(triphenylphosphine) palladium(0); Pd/C is palladium on carbon;PDC is pridinium dichromate; PE is petroleum ether; PMB is4-methoxybenzyl; PPh₃ is triphenylphosphine; prep-HPLC is preparativehigh performance liquid chromatography; prep-TLC is preparativethin-layer chromatography; Py is pyridine; TBAF is tetra-n-butylammoniumfluoride; TBSCl is tert-butyldimethylsilyl chloride; TEA istriethylamine; TFA is trifluoroacetic acid; THF is tetrahydrofuran; THPis tetrahydropyranyl; TLC is thin-layer chromatography; TSA isp-toluenesulfonic acid monohydrate, and TsCl is p-toluenesulfonylchloride.

Intermediate Preparations General Procedures

Procedure A (Amide Coupling)

To a solution of amine and TEA in the indicated solvent is added acylchloride dropwise at room temperature. After stirring for 16 hours, themixture is concentrated.

Procedure B (Suzuki Coupling)

To a solution of aryl halide in the indicated solvent is added boronicacid or ester, carbonate base, and palladium catalyst at roomtemperature. After stirring at 100° C. overnight, the mixture is cooledand concentrated.

Procedure C (Sodium Borohydride Reduction)

To a solution of aldehyde in the indicated solvent is added sodiumborohydride at 0° C. After stirring at room temperature for 2 hours,water is added and the mixture is concentrated.

Procedure D (DIBAL-H Reduction)

To a solution of ester in THF is added DIBAL-H dropwise at 0° C. Afterstirring at room temperature for 2 hours, water, 15% NaOH solution,water, and anhydrous sodium sulfate are added sequentiallly at 0° C. Theresulting slurry is stirred at room temperature for 1 hour and thenfiltered. The filter cake is washed with EA and the filtrate isconcentrated.

Procedure E (LAH Reduction)

To a solution of ester in THF is added LAH at 0° C. After stirring atroom temperature for 3 hours, water, 15% NaOH solution and water areadded sequentially. The mixture is then stirred at room temperature for15 minutes, filtered, and concentrated.

Procedure F (Alcohol Chlorination)

To a solution of alcohol in the indicated solvent is added thionylchloride dropwise at 0° C. After stirring at room temperature for 20minutes, the mixture is concentrated.

Procedure G (DMP Oxidation)

To a solution of alcohol in DCM is added DMP. Water is optionally addedto facilitate the reaction. After stirring for 1 hour, the mixture isconcentrated and EA and 10% sodium thiosulfate are added. The layers areseparated and the organic layer is washed with brine, dried overanhydrous sodium sulfate, and concentrated.

Preparation of A

Preparation of A1

Following Procedure A using 1 (1.0 g, 8.7 mmol), TEA (1.35 mL, 10.4mmol), DCM (10 mL), and BzCl (1.1 mL, 9.5 mmol), then purify with silicagel column chromatography (EA:PE=1:4) to give A1 as an oil (900 mg, 43%yield). (MS: [M+H]⁺220.1)

The following compounds are prepared by essentially the same method asfor A1.

Intermediate Structure MS A2

[M + H]⁺ 221.1 A3

[M + H]⁺ 221.1 A4

[M + H]⁺ 221.1Preparation of A5

Step 1: Alkene 3

Following Procedure B using 2 (1 g, 4.81 mmol), dioxane (9 mL), water (1mL), vinylboronic acid pinacol ester (888 mg, 5.77 mmol), sodiumcarbonate (1.27 g 12.02 mmol), and Pd(PPh₃)₄, then purify with silicagel column chromatography to give 3 as an oil (680 mg, 91% yield). (MS:[M+H]⁺ 156.1) Step 2: aldehyde 4

To a solution 3 (680 mg, 4.38 mmol) in MeOH/DCM (15 mL/15 mL) at −78° C.is bubbled with ozone slowly until a blue color persists. The solutionis then purged with nitrogen for 15 minutes before treated with sodiumbicarbonate (200 mg) and dimethyl sulfide (1.5 mL). After stirring atroom temperature overnight, the mixture is diluted with water (30 mL)and extracted with DCM (30 mL×3). The combined organic layers are driedover anhydrous sodium sulfate, filtered, and concentrated to give curde4 as a yellow oil (500 mg, 73% yield). (MS: [M+H]⁺ 158.1)

Step 3: A5

Following Procedure C using crude 4 (1.0 g, 6.35 mmol), MeOH, and sodiumborohydride (360 mg, 9.55 mmol), then quench with water (1 mL) andpurify with silica gel column chromatography (MeOH:DCM=1:50) to give A5as a solid (650 mg, 65% yield). (MS: [M+H]⁺ 160.1)

The following compounds are prepared by essentially the same method asfor A5.

Intermediate Structure MS A6

[M + H]⁺ 126.1 A7

[M + H]⁺ 203.1Preparation of A8

Step 1: Silyl Ether 6

To a solution of 5 (288 mg, 2.0 mmol) in THF is added DMAP (244 mg, 2.0mmol), TEA (0.25 mL, 2.0 mmol), and TBSCl (600 mg, 4.0 mmol). Afterstirring at room temperature for 16 hours, the mixture is concentratedand purified by silica gel column chromatography (MeOH:DCM=1:100) togive 6 as a white solid (400 mg, 78% yield). (MS: [M+H]⁺ 259.1)

Step 2: Pyrazole 7

A mixture of 6 (258 mg, 1.0 mmol), pyrazole, cesium carbonate (656 mg,2.0 mmol), CuI (19 mg, 0.1 mmol), and 1,10-phenanthroline (18 mg, 0.1mmol), in DMSO (5 mL) is react at 130° C. under microwave irradiationfor 45 minutes. After cooling to room temperature, the mixture isdiluted with EA (20 mL), washed with water (50 mL×3), dried overanhydrous sodium sulfate, filtered, concentrated, and purify by silicagel column chromatography (MeOH:DCM=1:100) to give 7 as a white solid(80 mg, 27% yield). (MS: [M+H]⁺ 291.2)

Step 3: A8

To a solution of 7 (80 mg 0.276 mmol) in THF (2 mL) is added TBAF (86mg, 0.331 mmol) at room temperature. After stirring at room temperaturefor 1 hour, the mixture is concentrated and purified by silica gelcolumn chromatography (MeOH:DCM=1:30) to give A5 as a white solid (48mg, 100% yield). (MS: [M+H]⁺ 177.1)

The following compounds are prepared by essentially the same method asfor A8.

Intermediate Structure MS A9

[M + H]⁺ 203.1 A10

—Preparation of A11

Step 1: Aldehyde 8

To a solution of 5 (500 mg, 3.47 mmol) in DCM is added activatedmanganese(IV) oxide (1.5 g, 17.4 mmol) at room temperature. Afterstirring at 40° C. for 4 hours, the mixture is filtered and concentratedto give crude 8 as a solid (400 mg, 80%). (MS: [M+H]⁺ 143.0)

Step 2: Imidazole 9

A mixture of 8 (50 mg, 0.35 mmol), imidazole (47 mg, 0.7 mmol), andpotassium carbonate (138 mg, 1.05 mmol) in DMF (2 mL) is stirred at 50°C. for 16 hours. The mixture is then diluted with EA (20 mL), washedwith aqueous lithium chloride solution (20 mL×3), dried over anhydroussodium sulfate, filtered, concentrated, and purified by silica gelcolumn chromatography (MeOH:DCM=1:50) to give 9 as a white solid (70 mg,100% yield). (MS: [M+H]⁺ 175.1)

Step 3: A11

Following Procedure C using 9 (70 mg, 0.4 mmol), MeOH, and sodiumborohydride (15.2 mg, 0.4 mmol), then quench with water (0.25 mL) andpurify with prep-TLC (MeOH:DCM=1:30) to give A11 as a white solid (50mg, 71% yield). (MS: [M+H]⁺177.1)

The following compound is prepared by essentially the same method as forA11.

Intermediate Structure MS A12

[M + H]⁺ 198.1Preparation of A13

Following Procedure C using 10 (1.0 g, 8.12 mmol), MeOH (10 mL), andsodium borohydride (615 mg, 16.25 mmol), then purify with silica gelcolumn chromatography (MeOH:DCM=1:20) to give A13 as a white solid. (300mg, 30% yield). (MS: [M+H]⁺ 126.1)

The following compounds are prepared by essentially the same method asfor A13.

Intermediate Structure MS A14

[M + H]⁺ 154.1 A15

[M + H]⁺ 110.0 A16

[M + H]⁺ 125.1Preparation of A17

Step 1: Pyridine 13

To a solution of 11 (600 mg, 3.32 mmol) in THF (15 mL) is added 12 (696mg, 6.40 mmol) and TEA (1.34 mL, 9.60 mmol) at room temperature. Afterstirring at 25° C. for 2 hours, the mixture is concentrated and purifiedby silica gel column chromatography (EA:PE=1:10 to 1:5) to give 13 (819mg, 98% yield) as a white solid. (MS: [M+H]⁺ 259.0)

Step 2: A17

Following Procedure D using 13 (819 mg, 3.17 mmol), THF (5 mL), DIBAL-H(1.5 M in toluene, 8.4 mL, 12.6 mmol), then quench with water (0.50 mL),15% NaOH solution (0.50 mL), water (1.26 mL), and anhydrous sodiumsulfate (5 g), and purify with silica gel column chromatography(EA:PE=1:1) to give A17 as a white solid (610 mg, 89% yield). (MS:[M+H]⁺ 217.0)

The following compounds are prepared by essentially the same method asfor A17.

Intermediate Structure MS A18

[M + H]⁺ 140.1 A19

[M + H]⁺ 166.1 A20

[M + H]⁺ 168.1 A21

[M + H]⁺ 182.1 A22

[M + H]⁺ 284.1 A23

[M + H]⁺ 184.1 A24

[M + H]⁺ 141.1 A25

[M + H]⁺ 157.0 A26

[M + H]⁺ 216.1 A27

[M + H]⁺ 217.1 A28

[M + H]⁺ 217.1 A29

[M + H]⁺ 154.1 A30

[M + H]⁺ 180.1 A31

[M + H]⁺ 194.1 A32

[M + H]⁺ 295.2 A33

[M + H]⁺ 196.1 A34

[M + H]⁺ 209.1Preparation of A35

Following Procedure B using 5 (150 mg, 1.04 mmol), 4-pyridinylboronicacid (191 mg, 1.56 mmol), sodium carbonate (220 mg, 2.1 mmol), dioxane(5 mL), water (0.5 mL), and Pd(dppf)Cl₂ (50 mg, 0.07 mmol), react at 90°C. for 4 hours and then purify with silica gel column chromatography(EA:PE=1:2) to give A35 as a solid (100 mg, 78% yield). (MS: [M+H]⁺188.1)

Preparation of A36:

Step 1: Ester 15

To a solution of 14 (20 g, 144 mmol) in MeOH (250 mL) is added thionylchloride (34.2 g, 288 mmol) at 0° C. After stirring at room temperaturefor 12 hour, the mixture is concentrated and then partitioned betweensaturated aqueous sodium bicarbonate (100 mL) and Et₂O (100 mL). Theaqueous layer is extracted with Et₂O (50 mL×3). The combined organiclayers are dried over anhydrous sodium sulfate, filtered, andconcentrated to give crude 15 (10 g 45% yield) as a white solid. (MS:[M+H]⁺ 154.1)

Step 2: Ester 16

To a mixture of crude 15 (2 g 13.1 mmol), phenylboronic acid (1.93 g,15.7 mmol), TEA (2.64 g, 26.1 mmol), Py (2.07 g, 26.1 mmol) in DCM (20mL) is added Cu(OAc)₂ (3.56 g, 19.6 mmol). After reacting at roomtemperature overnight under oxygen, the mixture is filtered,concentrated, and purify by silica gel column chromatography(MeOH:DCM=1:50) to give 16 as a yellow solid (2.3 g, 77% yield). (MS:[M+H]⁺ 230.1)

Step 3: A36

To a solution of 16 (500 mg, 2.18 mmol) in THF (10 mL) is added lithiumborohydride (2 M in THF, 1.64 mL, 3.28 mmol) dropwise at 0° C. Afterstirring at room temperature for 30 minutes, MeOH (15 mL) and water (3mL) are added at 0° C. The mixture is then stirred at room temperaturefor 30 minutes before concentrated and purified by silica gel columnchromatography (MeOH:DCM=1:50) to give A36 as a yellow solid (400 mg,91% yield). (MS: [M+H]⁺ 202.1)

Preparation of A37

Step 1: Ester 17

A mixture of 14 (500 mg, 3.27 mmol), potassium carbonate (901 mg, 6.54mmol) and 2-iodopropane (555 mg, 3.27 mmol) in DMF (3 mL) is stirred atroom temperature overnight. The mixture is then diluted with water (5mL) and extracted with EA (10 mL×3). The combined organic layers aredried over anhydrous sodium sulfate, filtered, and concentrated to givecrude 17 as a yellow oil (446 mg, 70% yield). (MS: [M+H]⁺ 196.1)

Step 2: A37

Following the procedure for A36 using crude 17 (400 mg, 2.05 mmol), THF(10 mL), and lithium borohydride (2 M in THF solution, 1.55 mL, 3.1mmol), then purify with silica gel column chromatography (MeOH:DCM=1:50)to give A37 as a yellow solid (200 mg, 58% yield). (MS: [M+H]⁺ 168.1)

Preparation of A38

Step 1: Acid 19

To a solution of 18 (800 mg, 3.40 mmol) in MeOH (20 mL) and water (20mL) is added NaOH (408 mg, 10.2 mmol). After stirring at roomtemperature overnight, the mixture is concentrated and the residue isdissolved in water (10 mL) followed by acidified to pH 1 by addition ofconcentrated aqueous HCl. The precipitate is collected by filtration anddried to give crude 19 (600 mg, 91% yield). (MS: [M+H]⁺ 236.0)

Step 2: A38

To a solution of crude 19 (100 mg, 0.48 mmol) in THF (5 mL) is addedisobutyl chloroformate (0.05 mL, 0.58 mmol) followed by NMM (0.06 mL,0.58 mmol) at −10° C. After stirring for 10 minutes, the mixture isfiltered and sodium borohydride (37 mg, 0.96 mmol) in water (0.2 mL) isadded dropwise at 0° C. After stirring at room temperature for 20minutes, the mixture is concentrated and the residue is partitionedbetween EA (20 mL) and water (10 mL). The organic layer is washed withbrine (10 mL), dried over anhydrous sodium sulfate, concentrated, andpurified by silica gel column chromatography (MeOH:DCM=1:100) to giveA38 as a colorless oil (50 mg, 74% yield). (MS: [M+H]⁺ 194.1)

Preparation of A39:

Step 1: Ester 20

Following Procedure B using 11 (500 mg, 2.67 mmol), dioxane (10 mL),phenylboronic acid (650 mg, 5.36 mmol), potassium carbonate (1.85 g,13.4 mmol), and Pd(dppf)Cl₂ (50 mg), then purified by silica gel columnchromatography (EA:PE=1:100 to 1:50) to give 20 as a white solid (400mg, 65% yield). (MS: [M+H]⁺ 229.1)

Step 2: A39

Following Procedure D using 20 (400 mg, 1.75 mmol), THF (20 mL), andDIBAL-H (1.5 M in toluene, 4.1 mL, 6.13 mmol), then purify with silicagel column chromatography (EA:PE=1:1) to give A39 as a white solid (240mg, 74% yield). (MS: [M+H]⁺ 187.1)

Preparation of A40

Step 1: Ester 22

A solution of 21 (1.53 g, 9.8 mmol) and N,N-dimethylformamide dimethylacetal (2 g, 16.8 mmol) in dioxane (20 mL) is heated at 100° C. for 4hours. The mixture is then cooled, concentrated, co-evaporated withtoluene to give crude 22 as a yellow oil (2.1 g, 78% yield). (MS: [M+H]⁺214.1)

Step 2: Pyrimidine 23

To a solution of 22 (1 g, 4.73 mmol) and guanidine hydrochloride (452mg, 4.73 mmol) in n-butanol (40 mL) is added NaOH (189 mg, 4.73 mmol).After stirring at 120° C. for 2 hours, the mixture is concentrated andthe residue is dissolved EA (100 mL), washed with brine (30 mL×3), driedover anhydrous sodium sulfate, filtered, concentrated, and trituratedwith n-hexane (30 mL). The solid is collected by filtration, washed withhexane (3 mL×3), and dried to give 23 as a pale yellow solid (400 mg,40% yield). (MS: [M+H]⁺ 208.1)

Step 3: A40

Following Procedure D using 23 (100 mg, 0.48 mmol), THF (5 mL), andDIBAL-H (1.5 M in toluene, 1.3 ml, 1.93 mmol), but quench with 15%aqueous NaOH solution (0.5 mL) to give crude A40 as a white solid (60mg, 40% yield). (MS: [M+H]⁺166.1)

Preparation of A41

Step 1: Aldehyde 25

To a solution of 24 (1.0 g, 10.4 mmol) in DMF (10 mL) is added NaH (625mg, 15.6 mmol) at 0° C. After stirring at room temperature for 1 hour,2-(trimethylsilyl)ethoxymethyl chloride (2.0 g, 12.5 mmol) is addeddropwise at 0° C. The mixture is then stirred for 16 hours beforediluted with EA (50 mL), washed with aqueous lithium chloride solution(20 mL×4), dried over anhydrous sodium sulfate, filtered, concentrated,and purified by silica gel column chromatography (MeOH:DCM=1:10) to give25 as a brown oil (1.0 g, 43% yield). (MS: [M+H]⁺ 227.1)

Step 2: A41

Following Procedure C using 25 (1.0 g, 4.4 mmol), THF (10 mL), andsodium borohydride (152 mg, 6.6 mmol), then quench with water (0.1 mL)and purify with silica gel column chromatography (MeOH:DCM=1:10) to giveA41 as a brown oil (450 mg, 45% yield). (MS: [M+H]⁺ 229.1)

Preparation of A42

Following Procedure C using 26 (408 mg, 3.0 mmol), THF (5 mL), MeOH (1mL), and sodium borohydride (230 mg, 6.0 mmol), then quench with water(0.1 mL) and purify with silica gel column chromatography(MeOH:DCM=1:30) to give A42 as an oil (220 mg, 53% yield). (MS: [M+H]⁺139.1)

Preparation of A43

Step 1: Aldehyde 27

Following Procedure A using isonicotinoyl chloride (2.76 g, 19.5 mmol),dioxane (20 mL), 10 (800 mg, 6.5 mmol), and TEA (5.42 mL, 39 mmol),react at 100° C. and then dilute the mixture with EA (20 mL), wash withwater (30 mL) and brine (50 mL), concentrate, and purify with silica gelcolumn chromatography (MeOH:DCM=1:50) to give 27 as a white solid (400mg, 27% yield). (MS: [M+H]⁺ 229.1)

Step 2: A43

Following Procedure C using 27 (300 mg, 1.31 mmol), MeOH (5 mL), andsodium borohydride (75 mg, 1.97 mmol), then purify with silica gelcolumn chromatography (MeOH:DCM=1:20) to give A43 as a white solid (180mg, 60% yield). (MS: [M+H]⁺ 231.1)

Preparation of A44

Step 1: Aldehyde 29

To a mixture of 28 (150 mg, 1.25 mmol) in 50% aqueous H₂SO₄ solution (2mL) is added Pd/C (5 wt. %, 15 mg). After stirring at room temperatureunder hydrogen for 8 hours, the mixture is neutralized with solid sodiumbicarbonate at 0° C. and extracted with EA (30 mL×5). The combinedorganic layers are dried over anhydrous sodium sulfate, filtered, andconcentrated to give crude 29 as a white solid (100 mg, 65% yield). (MS:[M+H]⁺ 124.0)

Step 2: A44

Following Procedure C using 29 (100 mg, 0.8 mmol), MeOH (0.5 mL), THF(1.5 mL), and sodium borohydride (34 mg, 0.9 mmol), then purify withsilica gel column chromatography (MeOH:DCM=1:50) to give A44 as a whitesolid (90 mg, 88% yield). (MS: [M+H]⁺ 126.1)

Preparation of A45

Step 1: Enol Ether 31

A mixture of 30 (1.0 g 5.17 mmol) in DMF (20 mL) is addedtributyl(1-ethoxyvinyl)tin (1.8 g 5.17 mmol) and Pd(PPh₃)₄ (150 mg 0.13mmol). After stirring at 100° C. for 2 hours, saturated aqueouspotassium fluoride solution (20 mL) is added and the mixture is stirredfor 30 minutes. The mixture is then diluted with EA (50 mL), washed withbrine (30 mL×3), dried over anhydrous sodium sulfate, filtered, andconcentrated to give crude 31 as a white solid (560 mg, 66% yield). (MS:[M+H]⁺ 185.0)

Step 2: Ketone 32

To a solution of crude 31 (560 mg 3.0 mmole) in THF (20 mL) is addedaqueous HCl solution (1 M, 5 mL) at room temperature. After stirring atroom temperature for 5 hours, the mixture is concentrated and theresidue is partitioned between saturated aqueous sodium bicarbonate (20mL) and EA (100 mL). The organic layer is washed with brine (20 mL×3),dried over anhydrous sodium sulfate, filtered, concentrated, andpurified by silica gel column chromatography (DCM:PE=1:1) to give 32 asa white solid (450 mg, 95% yield). (MS: [M+H]⁺ 157.0)

Step 3: Alcohol 33

To a solution of 32 (130 mg, 0.67 mmol) in EtOH (5 mL) is addedethanolamine (50 mg, 0.67 mmol) at room temperature. After stirring at80° C. for 30 minutes, the mixture is cooled and concentrated to give 33as a colorless oil (162 mg, 100% yield). (MS: [M+H]⁺ 182.1)

Step 4: A45

Following Procedure C using 33 (160 mg, 0.87 mmole), MeOH (5 mL), andsodium borohydride (15.5 mg, 0.41 mmol), then purify with silica gelcolumn chromatography (DCM) to give A45 as a colorless oil (150 mg, 99%yield). (MS: [M+H]⁺ 184.1)

Preparation of A46

Step 1: Pyrimidine 34

To a solution of 30 (580 mg, 3.0 mmol) in n-butanol (6 mL) is addedaniline (335 mg, 3.6 mmol). After stirring at 110° C. for 4 hours, themixture is concentrated and purified by silica gel column flashchromatography (EA:PE=1:10) to give 34 as an off-white solid (500 mg,66% yield). (MS: [M+H]⁺ 250.0)

Step 2: Aldehyde 35

A solution of 34 (500 mg, 2.0 mmol) and NaH (72 mg, 3.0 mmol) in THF (5mL) is stirred at −70° C. for 15 minutes before n-BuLi (2.5 M, 1.2 mL,3.0 mmol) is added dropwise. After stirring for 1 hour, DMF (1 mL) isadded dropwise and the mixture is stirred at room temperature for 1 hourbefore pouring into saturated ammonium chloride solution (20 mL). Themixture is then extracted with EA (30 mL×3). The combined organic layersare dried over anhydrous sodium sulfate, filtered, concentrated, andpurified by silica gel column chromatography (EA:PE=1:10) to give 35 asa white solid (150 mg, 37% yield). (MS: [M+H]⁺ 200.0)

Step 3: A46

Following Procedure C using 35 (150 mg, 0.7 mmol), MeOH (2 mL), andsodium borohydride (42 mg, 1.1 mmol), then purify with silica gel columnchromatography (EA:PE=1:2) to give A46 as a white solid (115 mg, 76%yield). (MS: [M+H]⁺ 202.0)

Preparation of A47

Step 1: Pyrimidine 37

To a solution of 36 (400 mg, 2.5 mmol) in HOAc (5 mL) is added Fe (700mg, 12.5 mmol). After stirring at 75° C. for 2 hours, the mixture iscooled to room temperature, filtered, concentrated, and purified bysilica gel column chromatography (EA:PE=1:5) to give 37 as as an oil(320 mg, 98% yield). (MS: [M+H]⁺ 130.0)

Step 2: Pyrimidine 38

To a solution of 37 (300 mg, 2.3 mmol) in MeCN (1.5 mL) and THF (1.5 mL)are added TEA (468 mg, 4.6 mmol), DMAP (284 mg, 2.3 mmol), anddi-tert-butyl dicarbonate (2.5 g, 11.6 mmol). After stirring at roomtemperature for 2 hours, the mixture is concentrated and purified bysilica gel column chromatography (EA:PE=1:100) to give 38 as a whitesolid (380 mg, 49% yield). (MS: [M+H]⁺ 330.1)

Step 3: Ester 39

To a solution of 38 (380 mg, 1.1 mmol) and TEA (348 mg, 3.4 mmol) inMeOH (5 mL) is added Pd(dppf)Cl₂ (169 mg, 0.2 mmol). After stirring at100° C. under CO (60 psi) for 16 hours, the mixture is cooled to roomtemperature, filtered, concentrated, and purified by silica gel columnchromatography (MeOH:DCM=1:50) to give 39 as a light pink solid (260 mg,89% yield). (MS: [M+H]⁺ 254.1)

Step 4: A47

Following Procedure C using 39 (200 mg, 0.8 mmol), MeOH (3 mL), andsodium borohydride (45 mg, 1.2 mmol), and quench with saturated ammoniumchloride solution (1 mL), extract with EA (20 mL), dry over anhydroussodium sulfate, filter, concentrate, and purify with silica gel columnchromatography (MeOH:DCM=1:20) to give A47 as an off-white solid (150mg, 84% yield). (MS: [M+H]⁺ 226.1)

Preparation of A48

Step 1: Ester 41

A mixture of 40 (10 g 26.8 mole) and N,N-dimethylformamide dimethylacetal (10 g, 84.5 mmol) is stirred at room temperature overnight. Themixture is then concentrated, co-evaporated with toluene (10 mL×3) togive crude 41 as a yellow oil (14 g, 100% yield). (MS: [M+H]⁺ 186.1)

Step 2: Pyrimidine 42

To a solution of 41 (3 g, 16.2 mmol) and guanidine hydrochloride (1.55g, 16.2 mmol) in n-butanol (50 mL) is added NaOH (648 mg, 16.2 mmol).After stirring at 120° C. for 2 hours, the mixture is concentrated andthe residue is dissolved in EA (100 mL), washed with water (50 mL) andbrine (50 mL), dried over anhydrous sodium sulfate, filtered,concentrated, and triturated with n-hexane (50 mL). The solid iscollected by filtration, washed with hexane (5 mL×3), and dried to give42 as a white solid (800 mg, 28% yield). (MS: [M+H]⁺ 182.1)

Step 3: Acid 43

To a solution of 42 (500 mg, 2.8 mmol) in MeOH (20 mL) and water (20 mL)is added NaOH (331 mg, 8.3 mmol). After stirring at room temperatureovernight, the mixture is concentrated and the residue is dissolved inwater (10 mL) and acidified to pH 1 with concentrated aqueous HCl. Theprecipitate is collected by filtration and dried to give 43 (330 mg, 85%yield). (MS: [M+H]⁺ 154.1)

Step 4: A48

To a solution of 43 (100 mg, 0.65 mmol) in THF (5 mL) is added isobutylchloroformate (89 mg, 0.65 mmol) followed by NMM (66 mg, 0.65 mmol) at−10° C. After stirring for 10 minutes, the precipitate is removed byfiltration. To the filtrate is added a solution of sodium borohydride(37 mg, 0.96 mmol) in water (0.2 mL) at 0° C. After stirring at roomtemperature for 20 minutes, the mixture is concentrated and the residueis partitioned between EA (20 mL) and water (10 mL). The organic layeris washed with brine (10 mL), dried over anhydrous sodium sulfate,filtered, concentrated, and purified by silica gel column chromatography(MeOH:DCM=1:100) to give A48 as a colorless oil (60 mg, 67% yield). (MS:[M+H]⁺ 140.1)

Preparation of A49

To a solution of 44 (100 mg, 0.9 mmol) in THF (2 mL) is added MgMeBr (1M, 1.1 mL, 1.1 mmol) dropwise at −70° C. After stirring for 1 hour, EtOH(1 mL) is added at 0° C. and then the mixture is acidified with 2 M HClto pH 6. The mixture is then extracted with EA (10 mL×2). The combinedorganic layers are dried over anhydrous sodium sulfate, filtered,concentrated, and purified by silica gel column chromatography(MeOH:DCM=1:50) to give A49 as a colorless oil (80 mg, 70% yield). (MS:[M+H]⁺ 125.1)

Preparation of A50

Step 1: Pyrimidine 46

To a solution of 45 (5.0 g, 28.7 mmol) in THF (50 mL) are addeddi-tert-butyl dicarbonate (13.8 g, 63.2 mmol), TEA (12.0 mL, 86 mmol),and DMAP (360 mg, 2.87 mmol). After stirring at 60° C. for 16 hour, themixture is concentrated and purified by silica gel column chromatography(EA:PE=1:5) to give 46 as a white solid (9.0 g, 84% yield). (MS: [M+H]⁺374.1)

Step 2: Enol Ether 47

Following the procedure for 31 using 46 (3.0 g, 8.0 mmol), DMF (30 mL),tributyl(1-ethoxyvinyl)stannane (4.3 g, 12.0 mmol), and Pd(PPh₃)₂Cl₂(281 mg, 0.4 mmol), react at 80° C. for 16 hours and then purify withsilica gel column chromatography (EA:PE=1:8) to give 47 as an oil (2.49g, 85% yield). (MS: [M+H]⁺ 366.2)

Step 3: Ketone 48

To a solution of 47 (2.49 g, 6.82 mmol) in THF (5 mL) is added aqueousHCl solution (1 M, 2 mL, 2.0 mmol) at room temperature. After stirringfor 3 hours, the mixture is concentrated and purified by silica gelcolumn chromatography (EA:PE=1:5) to give 48 as a white solid (2.1 g,91% yield). (MS: [M+H]⁺ 338.2)

Step 4: A50

Following Procedure C using 48 (1.0 g, 2.97 mmol), THF (8 mL), MeOH (1mL), and sodium borohydride (26 mg, 0.68 mmol), then purify with silicagel column chromatography (EA:PE=1:1) to give A50 as a white solid (819mg, 82% yield). (MS: [M+H]⁺ 340.2)

Preparation of AA1

Step 1: Pyrimidine 51

To a suspension of 50 (3.87 g, 40.9 mmol) in EtOH (10 mL) is added asolution of sodium methoxide (2.2 g, 40.9 mmol) in EtOH (10 mL). Afterstirring at room temperature for 40 minutes, the mixture is filtered andthe solid is washed with EtOH (1 mL). The filtrate is then treated with49 (2.5 g, 20.5 mmol) and the resulting solid is collected by filtrationand dried to give 51 (700 mg, 26%). (MS: [M+H]⁺ 109.0)

Step 2: Aldehyde 52

To a solution of 51 (700 mg, 5.2 mmol) in water and H₂SO₄ is added Pd/C(10 wt. %, 543 mg). After stirring at room temperature under hydrogenfor 16 hours, the mixture is filtered through a pad of Celite and washedwith water. The filtrate is treated with ammonium hydroxide, and thesolid is collected by filtration and dried to give 52 (500 mg, 70%).(MS: [M+H]⁺ 138.1)

Step 3: AA1

Following Procedure C using 52 (500 mg, 3.6 mmol), MeOH (2 mL), THF (2mL), and sodium borohydride (138 mg, 3.6 mmol), then purify with silicagel column chromatography (DCM) to give AA1 as a white solid (250 mg,50%). (MS: [M+H]⁺ 140.0)

Preparation of AA2

Step 1: Pyrimidine 54

To a solution of 53 (500 mg, 2.68 mmol) in DMF is added potassiumcarbonate (555 mg, 4.02 mmol) and 2,4-dimethoxybenzylamine (500 mg, 2.99mmol). After stirring at 50° C. for 3 hours, the mixture is cooled,diluted with EA, and washed with saturated aqueous lithium chloridesolution (20 mL×3). The organic layer is dried over anhydrous sodiumsulfate, concentrated, and purified by silica gel column chromatographyto give 54 as a solid. (617 mg, 73%). (MS: [M+H]⁺ 318.1)

Step 2: Alcohol 55

Following Procedure E using 54 (617 mg, 1.95 mmol), THF, LAH (555 mg,4.02 mmol), and quenching with water (0.2 mL), 15% NaOH solution (0.2mL) and water (0.6 mL), then purify with silica gel columnchromatography to give 55 as an oil. (200 mg, 37%). (MS: [M+H]⁺ 276.1)

Step 3: Aldehyde 56

To a solution of 55 (200 mg, 0.73 mmol) in DCM (5 mL) is added activatedmanganese(IV) oxide (632 mg, 7.3 mmol). After stirring at roomtemperature for 3 hours, the mixture is filtered, concentrated, andpurified by silica gel column chromatography to give 56 as a white solid(180 mg, 90%). (MS: [M+H]⁺ 274.1)

Step 4: AA2

To a solution of 56 (180 mg, 0.66 mmol) in THF (3 mL) is added MeMgBr (3M in THF, 0.33 mL) at −78° C. After stirring for 2 hours, saturatedaqueous ammonium chloride solution is added and the mixture is extractedwith EA (10 mL×3). The combined organic layers are dried over anhydroussodium sulfate, filtered, concentrated, and purified by silica gelcolumn chromatography to give AA2 as a white solid (88 mg, 46%). (MS:[M+H]⁺290.1)

Preparation of AA3

Step 1: Pyrimidine 58

To a solution of 57 (2.0 g, 8.62 mmol) in MeCN (20 mL) is added2,4-dimethoxybenzylamine (1.43 g, 8.62 mmol) and potassium carbonate(2.37 g, 17.2 mmol). After stirring at 50° C. for 3 hours, the mixtureis cooled and concentrated. Ethanol (20 mL) is then added and theresulting suspension is stirred at room temperature for 1 hour. Thesolid is collected by filtration and washed with EtOH (1 mL) to give 58as a yellow solid (2.3 g, 72% yield). (MS: [M+H]⁺ 364.0)

Step 2: AA3

Following Procedure E using 58 (500 mg, 1.37 mmol), THF (50 mL), and LAH(104 mg, 2.74 moml), then quench with saturated aqueous ammoniumchloride solution (10 mL), extract with EA (50 mL×3), dry over anhydroussodium sulfate, filter, concentrate, and purify with silica gel columnchromatography (EA:PE=1:1) to give AA3 as an white solid (309 mg, 70%).(MS: [M+H]⁺ 322.2)

Prepared by essentially the same method as for AA2. (MS: [M+H]⁺ 173.6).

Preparation of AB2

Step 1: Ketone 60

A mixture of 59 (300 mg, 1.19 mmol), isopropenyl acetate (143 mg, 1.43mmol), tributyltin methoxide (458.5 mg, 1.43 mmol) and Pd(OAc)₂ intoluene (20 mL) is stirred at 100° C. for 16 hours. After cooling toroom temperature, the mixture is concentrated and purified by silica gelcolumn chromatography (EA:PE=1:10) to give 60 as a white solid (110 mg,40.3%). (MS: [M+H]⁺ 230.1)

Step 2: AB2

Prepared by essentially the same method as for A42. (MS: [M+H]⁺ 232.1)

Preparation of B

Preparation of B1

To a solution of 61 (1.5 g, 11.7 mmol) and NBS (2.3 g, 12.8 mmol) incarbon tetrachloride (30 mL) is added BPO (28 mg, 0.12 mmol). Afterstirring at 80° C. for 6 hours, the mixture is concentrated and purifiedby silica gel column chromatography (EA:PE=1:10) to give B1 as acolorless oil (850 mg, 35% yield). (MS: [M+H]⁺ 208.9)

Preparation of B2

Step 1: Pyrazole 62

To a solution of 61 (1.4 g 10.0 mmol) in THF (30 mL) is added NaH (480mg 12.0 mmol) followed by 2-(trimethylsilyl)ethoxymethyl chloride (2.5 g15.0 mmol) at 0° C. After stirring at room temperature overnight,saturated ammonium chloride solution is added and the mixture isextracted with EA (20 mL×3). The combined organic layers are dried overanhydrous sodium sulfate, filtered, concentrated, and purified by silicagel column chromatography (EA:PE=1:20 to 1:5) to give 62 as an oil (2.60g, 96% yield). (MS: [M+H]⁺271.1)

Step 2: Alcohol 63

Following Procedure D using 62 (2.00 g, 7.41 mmol), THF (30 mL), andDIBAL-H (1.5 M in toluene, 16.7 mL, 25.0 mmol) and quenching with water(1 mL), 15% NaOH solution (1 mL), water (2.4 mL), and anhydrous sodiumsulfate (20 g), then purify with silca gel column chromatography(EA:PE=1:5 to 1:3) to give 63 as an oil (1.3 g, 77% yield). (MS: [M+H]⁺229.3)

Step 3: B2

To a solution of 63 (160 mg, 0.70 mmol) in DCM (8 mL) is added TEA (0.2mL) and MsCl (0.065 mL, 1.05 mmol) at 0° C. After stirring at roomtemperature for 1 hour, saturated ammonium chloride solution is addedand the mixture is extracted with EA (8 mL×3). The combined organiclayers are dried over anhydrous sodium sulfate, filtered, concentrated,and purified by silica gel column chromatography (EA:PE=1:20 to 1:5) togive B2 as an oil (130 mg, 76% yield). (MS: [M+H]⁺ 247.2) Preparation ofB3

Step 1: Pyrimidine 64

Following Procedure B using 5 (200 mg, 1.4 mmol), cyclopropylboronicacid (356 mg, 4.15 mmol), sodium carbonate (440 mg, 4.15 mmol), dioxane(10 mL), water (1 mL), and Pd(PPh₃)₄ (80 mg, 0.07 mmol), react at 100°C. for 3 hours and then purify with silica gel column chromatography(EA:PE=1:10 to 10:1) to give 64 as a white solid (19 mg, 9% yield). (MS:[M+H]⁺ 151.1)

Step 2: B3

Following Procedure F using 64 (19 mg, 0.13 mmol), MeCN (2 mL), andthionyl chloride (0.1 mL) gives crude B3 as a white solid (21.3 mg, 100%yield). (MS: [M+H]⁺ 169.1)

The following compounds are prepared by essentially the same method asfor B3.

Intermediate Structure MS B4

[M + H]⁺ 206.0 B5

[M + H]⁺ 206.0Preparation of B6

Step 1: Alcohol 65

Following Procedure D using 57 (1.20 g, 5.17 mmol), THF (30 mL), andDIBAL-H (1.5 M in toluene, 9.0 mL, 13.1 mmol) and quenching with water(0.6 mL), 15% NaOH solution (0.6 mL), water (1.5 mL), then purify withsilica gel column chromatography (EA:PE=1:5 to 1:3) to give 65 as an oil(850 mg, 87% yield). (MS: [M+H]⁺ 190.1)

Step 2: B6

Following Procedure F using 65 (100 mg, 0.53 mmol), MeCN (5 mL), andthionyl chloride (0.20 mL, 2.75 mmol) gives crude B6 as a white solid(108 mg, 100% yield). (MS: [M+H]⁺ 208.9)

Preparation of B7

Step 1: Ester 66

To a solution of 57 (1.20 g 5.1 mmol) in MeOH (40 mL) is added NaOMe(330 mg, 6.08 mmol). After stirring at 50° C. overnight, the mixture isfiltered, concentrated, and purified by silica gel column chromatography(EA:PE=1:30 to 1:20) to give 66 as a white solid (1.02 g 93% yield).(MS: [M+H]⁺ 215.2)

Step 2: Alcohol 67

Following Procedure D using 66 (428 mg, 2.0 mmol), THF (30 mL), andDIBAL-H (1.5 M in toluene, 3.3 mL, 5.0 mmol) and quenching water (0.2mL), 15% NaOH solution (0.2 mL), water (0.5 mL), and anhydrous sodiumsulfate (4 g), then purify with silica gel column chromatography(EA:PE=1:5 to 1:3) to give 67 as an oil (260 mg, 70% yield). (MS: [M+H]⁺187.1)

Step 3: B7

Following Procedure F using 67 (372 mg, 2.0 mmol), MeCN (10 mL), andthionyl chloride (0.36 mL, 5.0 mmol) give crude B7 as a white solid (380mg, 100% yield). (MS: [M+H]⁺ 205.1)

Preparation of B8

Step 1: Ester 68

To a solution of 57 (1.16 g, 5.00 mmol) in THF (20 mL) is added sodiummethanethiolate (20 wt. % aqueous solution, 5.3 g, 15.0 mmol). Afterstirring at 50° C. overnight, the mixture is concentrated and purifiedby silica gel column chromatography (EA:PE=1:30 to 1:20) to give 68 as awhite solid (400 mg, 33% yield). (MS: [M+H]⁺ 245.1)

Step 2: Alcohol 69

Following Procedure D using 68 (400 mg, 1.64 mmol), THF (15 mL), andDIBAL-H (1.5 M in toluene, 2.7 mL, 4.1 mmol) and quenching with water(0.2 mL), 15% NaOH solution (0.2 mL), water (0.5 mL), and anhydroussodium sulfate (4 g), then purify with slica gel column chromatography(EA:PE=1:5 to 1:3) to give 69 as an oil (180 mg, 54% yield). (MS: [M+H]⁺203.1)

Step 3: B8

Following Procedure F using 69 (180 mg, 0.89 mmol), MeCN (8 mL), andthionyl chloride (0.20 mL, 2.75 mmol) gives crude B8 as a white solid(186 mg, 100% yield). (MS: [M+H]⁺ 220.2)

Preparation of B9

Following Procedure F using A49 (80 mg, 0.65 mmol), MeCN (3 mL), andthionyl chloride (0.5 mL) gives B9 as a white solid (91.2 mg, 100%yield). (MS: [M+H]⁺ 143.0)

Preparation of B10

Step 1: Alcohol 70

Following Procedure C using 32 (75 mg, 0.48 mmol), MeOH (5 mL), andsodium borohydride (36.2 mg, 0.96 mmol), and purify with silica gelcolumn chromatography (EA) to give 70 as a white solid (37 mg, 49%yield). (MS: [M+H]⁺ 159.0)

Step 2: B10

Following Procedure F using 70 (37 mg, 0.23 mmol), DCM (3 mL), andthionyl chloride (55 mg, 0.47 mmol) gives B10 as a white solid (41 mg,100% yield). (MS: [M+H]⁺ 177.0)

Preparation of B11

Step 1: Pyrimidine 71

To a solution of 32 (117 mg, 0.76 mmol) in THF (30 mL) is added TEA (383mg, 3.78 mmol) and methylamine hydrochloride (153 mg, 2.27 mmol). Afterstirring at room temperature overnight, the mixture is concentrated andpurified by silica gel column chromatography (EA:PE=1:4 to 1:1) to give71 as a pale yellow solid (100 mg, 89% yield). (MS: [M+H]⁺ 152.1)

Step 2: Pyrimidine 72

To a solution of 71 (100 mg 0.66 mmol), TEA (201 mg, 1.98 mmol) and DMAP(81 mg, 0.66 mmol) in THF (10 mL) is added di-tert-butyl dicarbonate(360 mg, 1.65 mmol). After stirring at room temperature overnight, themixture is concentrated and purified by silica gel column chromatography(EA:PE=1:10 to 1:1) to give 72 as a colorless oil (137 mg, 83% yield).(MS: [M+H]⁺ 252.1)

Step 3: Alcohol 73

Following Procedure C using 72 (200 mg, 0.80 mmol), MeOH (10 mL), sodiumborohydride (60 mg, 1.6 mmol), then purify with silica gel columnchromatography (EA) to give 73 as a colorless oil (127 mg, 64% yield).(MS: [M+H]⁺ 254.1)

Step 4: B11

Following Procedure F using 73 (60 mg, 0.24 mmol), DCM (5 mL), andthionyl chloride (38.82 mg, 0.28 mmol) gives crude B11 as a white solid(64 mg, 100%/yield). (MS: [M+H]⁺ 272.1)

Preparation of B12

Following Procedure F using A16 (24.8 mg, 0.20 mmol), MeCN (8 mL), andthionyl chloride (0.044 mL, 0.60 mmol) gives crude B12 as a white solid(26 mg, 100% yield). (MS: [M+H]⁺ 143.1)

The following compounds are prepared by essentially the same method asfor B12.

Intermediate Structure MS B13

[M + H]⁺ 142.0 B14

[M + H]⁺ 157.0Preparation of B15

Step 1: Pyrimidine 74

To a solution of A13 (2.0 g 15.9 mmol), TEA (6.47 g, 63.9 mmol), andDMAP (1.95 mmol) in THF (30 mL) is added di-tert-butyl dicarbonate (12.2g, 55.9 mmol). After stirring at room temperature overnight, the mixtureis concentrated and dissolved in EA (100 mL), washed with HCl solution(0.5 M, 30 mL) and brine (30 mL), dried over anhydrous sodium sulfate,filtered, concentrated, and purified by silica gel column chromatography(EA:PE=1:5) to give 74 as a white solid (680 mg, 10% yield). (MS: [M+H]⁺426.2)

Step 2: Alcohol 75

To a solution of 74 (680 mg, 1.6 mmol) in MeOH (30 mL) is added sodiummethoxide (518 mg, 9.6 mmol). After stirring at room temperatureovernight, the mixture is concentrated and partitioned between EA (50mL) and water (10 mL). The organic layer is O80 washed with brine (30mL), dried over anhydrous sodium sulfate, filtered, and concentrated togive crude 75 as a white solid (290 mg, 81% yield). (MS: [M+H]⁺ 226.1)

Step 3: B15

To a solution of 75 (290 mg, 1.3 mmol) in DCM (50 mL) is added Py (306mg, 3.9 mmol) and TsCl (368 mg, 1.9 mmol). After stirring at roomtemperature overnight, the mixture is concentrated and purified bysilica gel column chromatography (EA:PE=1:5) to give B15 as a whitesolid (240 mg, 77% yield). (MS: [M+H]⁺ 244.1)

The following compounds are prepared by essentially the same method asfor B15.

Intermediate Structure MS B16

[M + H]⁺ 258.1 B17

[M + H]⁺ 384.2 B18

[M + H]⁺ 312.1Preparation of B19

To a solution of A50 (100 mg, 0.29 mmol) in DCM (3 mL) is added TEA (44mg, 0.44 mmol) and MsCl (40 mg, 0.35 mmol) at 0° C. After stirring atroom temperature for 1 hour, the mixture is poured into a saturatedammonium chloride solution (10 mL) and extracted with DCM (20 mL×3). Thecombined organic layers are dried over anhydrous sodium sulfate,filtered, and concentrated to give crude B19 as an off-white solid (120mg, 98% yield). (MS: [M+H]⁺ 418.2)

Preparation of B20

Step 1: Pyrimidine 77

Following Procedure B using 11 (1.0 g, 5.36 mmol), 76 (2.48 g, 8.04mmol), sodium carbonate (568 mg, 5.36 mmol), dioxane (30 mL), water (3mL), and Pd(PPh₃)₄ (100 mg, 0.087 mmol), react at 80° C. for 16 hoursand then purify with silica gel column chromatography (EA:PE=1:1) togive 77 as a white solid (890 mg, 50% yield). (MS: [M+H]⁺ 334.2)

Step 2: Pyrimidine 78

To a solution of 77 (890 mg 2.67 mmol) in EA (5 mL) and EtOH (20 mL) isadded Pd/C (5 wt. %, 200 mg). After stirring at room temperature for 2hours, the mixture is filtered through a pad of Celite and concentratedto give crude 78 as a white solid (840 mg, 95% yield). (MS: [M+H]⁺336.2)

Step 3: Alcohol 79

Following Procedure D using 78 (110 mg, 0.34 mmol), THF (10 mL), andDIBAL-H (1.5 M in toluene, 0.68 mL, 1.03 mmol) and quenching withaqueous NaOH solution (0.5 mL, 15%) and anhydrous magnesium sulfate (2g), purify with silica gel column chromatography (EA) to give 79 as acolorless oil (50 mg, 50% yield). (MS: [M+H]⁺ 294.2)

Step 4: B20

Following the procedure for B19 using 79 (100 mg, 0.34 mmol), TEA (0.2mL, 1.36 mmol), THF (10 mL), and MsCl (0.1 mL, 1.36 mmol), purify withsilica gel column chromatography (DCM:PE=1:2 to 1:1) to give B20 as acolorless oil (80 mg, 59% yield). (MS: [M+H]⁺ 372.2)

Preparation of B21

To a solution of 70 (140 mg 0.9 mmol) in THF (10 mL) is added TEA (180mg 1.8 mmol) followed by MsCl (123 mg 1.1 mmol). After stirring at roomtemperature for 1 hour, the mixture is concentrated and the residue ispartitioned between EA (50 mL) and water (10 mL). The layers areseparated and the organic layer is washed with saturated aqueous sodiumbicarbonate (15 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated to give crude B21 as a white solid (200 mg, 96% yield).(MS: [M+H]⁺ 237.0)Preparation of B22

To a solution of 80 (500 mg, 2.70 mmol) and TEA (0.9 mL, 6.75 mmol) inDCM (10 mL) is added p-TsCl (514 mg, 2.70 mmol) at 0° C. After stirringat room temperature overnight, brine (20 mL) is added and the layers areseparated. The aqueous layer is extracted with DCM (20 mL×3). Thecombined organic layers are dried over anhydrous sodium sulfate,filtered, concentrated, and purified by silica gel column chromatography(EA:PE=1:5) to give B22 as a light yellow oil (400 mg, 44% yield). (MS:[M+H]⁺ 340.5)

Preparation of B23

Step 1: Ester 81

To a solution of 15 (1.0 g 6.53 mmol) in DMF (20 mL) is added potassiumcarbonate (1.8 g 13.1 mmol) and benzyl bromide (0.8 mL, 13.1 mmol) at 0°C. After stirring at room temperature overnight, the mixture is dilutedwith water (20 mL) and extracted with EA (40 mL×3). The combined organiclayers are washed with saturated aqueous ammonium chloride solution,dried over anhydrous sodium sulfate, filtered, concentrated, andpurified by silica gel column chromatography (EA:PE=1:10) to give 81 asa white solid (1.3 g, 82% yield). (MS: [M+H]⁺ 244.3)

Step 2: Aldehyde 82

To a solution of 81 (600 mg, 2.47 mmol) in DCM (30 mL) is added DIBAL-H(1.5 M toluene solution, 6.5 mL, 9.88 mmol) dropwise at 0° C. Afterstirring at room temperature for 2 h, saturated ammonium chlorideaqueous solution is added at 0° C. and the mixture is stirred at roomtemperature for 30 minutes, filtered, and concentrated to give crude 82as a white solid (300 mg, 57.0% yield). (MS: [M+H]⁺ 214.2)

Step 3: Alcohol 83

Following Procedure C using 82 (300 mg, 1.41 mmol), MeOH (10 mL), andsodium borohydride (106 mg, 2.81 mmol) gives 83 as a white solid (200mg, 66% yield). (MS: [M+H]⁺ 216.2)

Step 4: B23

Following the procedure for B22 using 83 (100 mg, 0.46 mmol), DCM (5mL), TEA (0.2 mL, 1.16 mmol), and TsCl (86 mg, 0.46 mmol) gives B23 as alight yellow oil (100 mg, 58% yield). (MS: [M+H]⁺ 370.4)

Preparation of B24

Step 1: Pyrimidine 84

Following the procedure for 68 using 53 (500 mg, 2.68 mmol), THF (15mL), and sodium methanethiolate (20 wt. %, 1.2 mL, 3.22 mmol), thenpurify with silica gel column chromatography (EA:PE=1:30 to 1:20) togive 84 as a white solid (400 mg, 75% yield). (MS: [M+H]⁺ 199.1)

Step 2: Acid 85

To a solution of 84 (400 mg, 2.0 mmol) in THF (4 mL) is added a solutionof NaOH (400 mg, 10.0 mmol) in water (4 mL) dropwise at 0° C. Afterstirring at room temperature for 2 hours, concentrated HCl is added toadjust the mixture to pH 5. The solid is then collected by filtration togive crude 85 as a white solid (250 mg, 74% yield). (MS: [M+H]⁺ 171.1)

Step 3: Alcohol 86

To a solution of crude 85 (237 mg, 1.39 mmol) in THF (20 mL) is addedisobutyl chloroformate (0.18 mL, 1.39 mmol) and NMM (154 mg, 1.52 mmol).After stirring at 0° C. for 20 min. The mixture is filtered andconcentrated. The residue is dissolved in THF (10 mL) and sodiumborohydride (43 mg, 1.11 mmol) in water (3 mL) is added dropwise at −15°C. After stirring for 20 minutes, saturated ammonium chloride solutionis added and the mixture is extracted with EA (10 mL×3). The combinedorganic layers are dried over anhydrous sodium sulfate, filtered,concentrated, and purified by silica gel column chromatography(EA:PE=1:5 to 1:3) to give 86 as an oil (100 mg, 46% yield). (MS: [M+H]⁺156.1)

Step 5: B24

Following Procedure F using 86 (95 mg, 0.60 mmol), MeCN (8 mL), andthionyl chloride (0.10 mL, 1.38 mmol) gives crude B24 as an oil (97 mg,100% yield). (MS: [M+H]⁺ 174.1)

Preparation of B25

Step 1: Ester 88

A mixture of 87 (2.0 g, 11.6 mmol), cesium carbonate (6.2 g, 19.0 mmol)in MeCN (20 mL) is stirred at room temperature for 3 hours before methyltrifluoromethanesulfonate (1.4 mL, 12.3 mmol) is added. After stirringat 70° C. overnight, the mixture is diluted with water (20 mL) andextracted with EA (20 mL×3). The combined organic layers are dried overanhydrous sodium sulfate, filtered, and concentrated to give 88 as ayellow oil (2 g, 93% yield).

Step 2: Pyrimidine 89

To a solution of crude 88 (2.0 g 10.8 mmol) in EtOH (20 mL) is addedS-methylisothiourea hemisulfate salt (5.99 g 21.6 mmol) and MeONa (1.16g, 21.6 mmol). After stirring at 80° C. overnight, the mixture isconcentrated and water (10 mL) is added. The solid is then collected byfiltration to give 89 as a white solid (1.0 g 41% yield). (MS: [M+H]⁺227.2)

Step 3: Alcohol 90

Following Procedure D using 89 (1.0 g, 4.4 mmol), THF (10 mL), andDIBAL-H (1.5 M toluene solution, 88 mL, 13.2 mmol) and quenching with15% aqueous NaOH solution (1 mL) gives crude 90 as a white solid (0.7 g,87% yield). (MS: [M+H]⁺185.1)

Step 4: B25

Following the procedure for B2 using 90 (235 mg 1.1 mmol), DCM (5 mL),TEA (0.34 mL, 2.2 mmol) and MsCl (0.18 mL, 2.2 mmol) and quenching withwater (3 mL) gives crude B25 as a yellow oil (258 mg 100% yield). (MS:[M+H]⁺ 203.1)

Preparation of B26

Step 1: Ester 92

A solution of 91 (3.0 g 15.2 mmol), Pd(OAc)₂ (342 mg, 1.52 mmol),Xantphos (881 mg, 1.52 mmol), and TEA (3.08 g, 30.5 mmol, 4.22 mL) inDMF (30 mL), and MeOH (15 mL) is stirred under CO (50 psi) at 80° C. for10 hours. After filteration and removal of MeOH, the mixture is dilutedwith EA (200 mL), washed with water (30 mL×3) and brine (30 mL×3), driedover anhydrous sodium sulfate, concentrated, and purified by silica gelcolumn chromatography (EA:PE=1:5 to 1:2) to give 92 as a yellow solid(2.7 g, 71% yield). (MS: [M+H]⁺ 177.1)

Step 2: Tosylate 93

To a solution of 92 (500 mg, 2.84 mmol) in DMF (10 mL) is added NaH(81.8 mg, 3.41 mmol) in portions at 0° C. After stirring at 15° C. for10 minutes, TsCl (650 mg, 3.41 mmol) is added and the mixture is stirredat 15° C. for 2 hours before ice is added. The mixture is then extractedwith EA (20 mL×2) and the combined organic layers are washed with brine(10 mL), dried over anhydrous sodium sulfate, filtered, and concentratedto give crude 93 as a white solid (0.8 g, 85% yield).

Step 3: Alcohol 94

Following Procedure E using 93 (500 mg, 1.51 mmol), THF (20 mL), and LAH(86 mg, 2.27 mmol) and quenching with water (0.2 mL) gives crude 94 as ayellow oil (0.4 g 88% yield). (MS: [M+H]⁺ 303.1)

Step 4: B26

Following the procedure for B19 using 94 (800 mg, 2.65 mmol), TEA (804mg, 7.95 mmol, 1.10 mL), DCM (20 mL), and MsCl (364 mg, 3.18 mmol, 0.25mL), then dilute the reaction mixture with DCM (20 mL) and washed withHCl (20 mL) and brine, dry over anhydrous sodium sulfate, andconcentrated give crude B26 as a yellow oil (800 mg, 80% yield).

Preparation of B27

Step 1: Indole 95

A mixture of 91 (900 mg, 4.54 mmol), DHP (1.91 g, 22.7 mmol, 2.1 mL),and TSA (86 mg, 0.45 mmol) in THF (5.00 mL) is stirred at 70° C. for 3hours. The mixture is then concentrated and purifed by silica gel columnchromatography (EA:PE=1:5 to 1:1) to give 95 as yellow oil (900 mg, 70%yield).

Step 2: Ester 96

Following the procedure for 92 using 95 (700 mg 2.48 mmol), Pd(OAc)₂(83.5 mg 0.37 mmol), Xantphos (215 mg 0.37 mmol), TEA (753 mg 7.44 mmol,1.03 mL), DMF (10 mL), and MeOH (10 mL), react 100° C. for 3 hours andpurify with silica gel column chromatography to give 96 as a yellow oil(300 mg 46% yield). (MS: [M+H]⁺ 178.1)

Step 3: Alcohol 97

Following Procedure E using 96 (300 mg, 1.15 mmol), THF (10 mL), and LAH(65 mg, 1.72 mmol) and quenching with water (0.2 mL) and solid sodiumsulfate gives crude 97 as a yellow oil (100 mg, 37% yield). (MS: [M+H]⁺150.1)

Step 4: B27

Following the procedure for B19 using 97 (90 mg, 0.386 mmol), TEA (117mg, 1.16 mmol, 0.16 mL), DCM (10 mL), and MsCl (53 mg, 0.463 mmol, 0.036mL) gives crude B27 (80 mg, 66.6% yield).

Preparation of B28

Step 1: Pyrimidine 98

Following the procedure for 31 using 30 (5.0 g, 25.9 mmol),tributyl(vinyl)tin (9.02 g, 28.4 mmol, 8.3 mL), Pd(PPh₃)₂Cl₂ (1.81 g2.58 mmol), and toluene (5 mL), react at 90° C. for 3 hours, quench withsaturated potassium fluoride (200 mL), and purify with silica gel columnchromatography (EA:PE=1:100 to 1:20) give 98 as a light yellow solid(2.46 g, 68% yield).

Step 2: Alcohol 99

To a solution of 98 (2.5 g 17.8 mmol) in THF (50 mL) is added boranedimethyl sulfide complex (10 M, 1.78 mL) at 0° C. After stirring for 1hour, NaOH (2.10 g 52.5 mmol) is added and the mixture is stirred at 16°C. for 16 hours. Saturated sodium sulfite (600 mL) is then added and themixture is extracted with EA (500 mL×3). The combined organic layers aredried over anhydrous sodium sulfate, concentrated, and purified bysilica gel column chromatography (EA/PE=1:10 to 1:5 to 1:2) to give 99as a white solid (1.00 g).Step 3: Pyrimidine 100

To a solution of 99 (1.0 g 6.31 mmol) in MeCN (10 mL) is added potassiumcarbonate (1.05 g, 7.57 mmol) and 2,4-dimethoxybenzylamine (1.27 g 7.57mmol, 1.14 mL). After stirring at 80° C. for 16 hours, the mixture isfiltered and concentrated. The residue is then dissolved in EA (20 mL)and washed with 5% aqueous citric acid solution. The aqueous layer isextracted with EA (20 mL) and the combined organic layers are dried overanhydrous sodium sulfate and concentrated to give crude 100 (350 mg).(MS: [M+H]⁺ 290.1)

Step 4: B28

Following the procedure for B15 using 100 (150 mg, 0.52 mmol), DCM (5mL), TsCl (297 mg, 1.56 mmol), and TEA (157 mg, 1.56 mmol, 0.22 mL),dilute the reaction mixture with DCM (50 mL), washed with water (20 mL)and sodium bicarbonate (20 mL×3), dried over sodium bicarbonate, andconcentrated to give crude B28 (300 mg). (MS: [M+H]⁺ 444.0)

Preparation of B29

Step 1: Pyrimidine 101

A mixture of 6 (300 mg, 1.16 mmol), 2-aminopyridine (142 mg, 1.51 mmol),cesium carbonate (755 mg, 2.32 mmol), Xantphos (268 mg, 0.464 mmol), andPd(dba)₂ (133 mg 0.232 mmol) in dioxane (6 mL) is stirred at 110° C. for12 hours. The mixture is then filtered, concentrated, and purified bysilica gel column chromatography (EA:PE=1:20 to 1:10) to give 101 as ayellow solid (200 mg, 55% yield). (MS: [M+H]⁺ 316.9)

Step 2: Alcohol 102

To a solution of 101 (200 mg, 0.632 mmol) in THF (10 mL) is added TBAF(1 M, 1.26 mL, 2.0 eq). After stirring at 16° C. for 16 hours, themixture is concentrated and purified by prep-HPLC to give 102 as a whitesolid (100 mg, 78% yield). (MS: [M+H]⁺ 203.0)

Step 3: B29

Following the procedure for B19 using 102 (100 mg, 0.495 mmol) in THF (5mL), TEA (150 mg, 1.48 mmol, 0.21 mL), and MsCl (113 mg, 0.99 mmol,0.077 mL), then dilute with DCM (100 mL), washed with water (30 mL) andbrine (50 mL×2), dried over anhydrous sodium sulfate, and concentratedto give crude B29 (100 mg).

Preparation BA1

Step 1: Pyrimidine 104

To a solution of 103 (2.42 g, 10.0 mmol) in THF (50 mL) is added DMAP(611 mg, 5.0 mmol), TEA (5.6 mL, 40.0 mmol) and di-tert-butyldicarbonate (6.9 mL, 30.0 mmol). After stirring at 60° C. overnight, themixture is cooled, concentrated, and purified by silica gel columnchromatography (EA:PE=1:50 to 1:30) to give 104 as a white solid (1.5 g,34%). (MS: [M+H]⁺ 442.1)

Step 2: Enol Ether 105

Following the procedure for 31 using 104 (500 mg, 1.13 mmol), DMF (20mL), Pd(dppf)Cl₂ (83 mg, 0.113 mmol), and tributyl(1-ethoxyvinyl)tin(0.49 mL, 1.47 mmol), react at 100° C. overnight and purify with silicagel column chromatography (EA:PE=1:50 to 1:20) to give 105 as an oil(180 mg, 37%). (MS: [M+H]⁺ 433.2)

Step 3: Ketone 106

To a solution of 105 (180 mg, 0.42 mmol) in THF (10 mL) is added HClsolution (6 N, 2 mL). After stirring at 60° C. for 2 hours, the mixtureis cooled, concentrated, and purified by silica gel columnchromatography (EA:PE=1:50 to 1:20) to give 106 as a white solid (120mg, 70%). (MS: [M+H]⁺ 406.1)

Step 4: Alcohol 107

Following Procedure C using 106 (72 mg, 0.18 mmol), MeOH (8 mL), sodiumborohydride (4.5 mg, 0.12 mmol), purify with silica gel columnchromatography (EA:PE=1:30 to 1:20) to give 107 as a white solid (20 mg,28%). (MS: [M+H]⁺ 408.1)

Step 5: BA1

Following Procedure F using 107 (20 mg, 0.049 mmol), MeCN (8 mL), andthionyl chloride (0.20 mL, 2.75 mmol) gives crude BA1 as a white solid(20 mg, 100%). (MS: [M+H]⁺ 426.1)

Preparation of BA2

Step 1: Silyl Ether 108

To a solution of 33 (220 mg, 1.21 mmol) in DCM (10 mL) is added TEA (0.4mL, 2.78 mmol), DMAP (200 mg 1.64 mmol), and TBSCl (252 mg 1.67 mmol).After stirring at room temperature for 16 hours, the mixture isconcentrated and is purified by silica gel column chromatography(EA:PE=1:3) to give 108 as a yellow oil (287 mg, 80%). (MS: [M+H]⁺296.2)

Step 2: Carbamate 109

To a solution of 108 (220 mg, 0.74 mmol) in THF (20 mL) is added DMAP(59 mg, 0.48 mmol) and di-tert-butyl dicarbonate (346 mg, 1.58 mmol).After stirring at room temperature for 16 hours, the mixture isconcentrated and purified by silica gel column chromatography(EA:PE=1:5) to give 109 as a yellow oil (290 mg, 99%). (MS: [M+H]⁺396.2)

Step 3: Alcohol 110

To a solution of 109 (280 mg 0.71 mmol) in THF (20 mL) and MeOH (2 mL)is added sodium borohydride (16 mg, 0.42 mmol). After stirring at roomtemperature for 3 hours, the mixture is diluted with EA (50 mL), washedwith water (20 mL×3), dried over anhydrous sodium sulfate, filtered andconcentrated to give crude 110 as a yellow solid (280 mg, 100%). (MS:[M+H]⁺ 398.2)

Step 4: BA2

Following the procedure for B2 using 110 (280 mg, 0.70 mmol), DCM (10mL), TEA (0.3 mL, 2.1 mmol), and MsCl (0.08 mL, 1.04 mmol), react atroom temperature for 5 hours and purify with silica gel columnchromatography (EA:PE=1:5) give BA2 as a yellow solid (200 mg, 68%).(MS: [M+H]⁺ 416.2)

Preparation of BA3

To a solution of 47 (2.4 g, 6.5 mmol) in THF (25 mL) and water (9 mL) isadded NBS (1.17 g, 6.5 mmol) at 0° C. After stirring for 1 hour, themixture is diluted with water and extracted with EA (20 mL×2). Thecombined organic layers are washed with saturated aqueous sodiumbicarbonate, brine and concentrated to give BA3 as a yellow solid (2.69g, 100%). (MS: [M+H]⁺ 416.1)

Preparation of BA4

Following Procedure F using 111 (70 mg, 0.18 mmol), DCM (5 mL), andthionyl chloride (43 mg, 0.36 mmol) gives crude BA4 as a white solid (72mg, 100%). (MS: [M+H]⁺ 328.1)

Preparation BA5

Prepared by essentially the same method as for B6.

Preparation of BB1

Step 1: Pyrimidine 114

A mixture of 30 (5.5 g, 33 mmol), 2,4-dimethoxybenzylamine (5.5 g, 33mmol) and potassium carbonate (4.97 g, 36 mmol) in DMF (30 mL) isstirred at 50° C. for 16 hours. The mixture is then cooled to roomtemperature and diluted with water (100 mL). The solid is collected byfiltration and recrystallized from EA/hexanes (1:4) to give 114 as awhite solid (9.4 g, 88% yield). (MS: [M+H]⁺ 324.0).

Step 2: Alkyne 115

A mixture of 114 (9.4 g, 30 mmol), ethynyltrimethylsilane (3.5 g, 36mmol), Pd(dppf)Cl₂ (1.1 g, 1.5 mmol), CuI (285 mg 1.5 mmol) and TEA (6.0g, 60 mmol) in THF (30 mL) is stirred at room temperature for 16 hours.The mixture is then filtered, diluted with EA (50 mL), washed with waterand brine, dried over anhydrous sodium sulfate, filtered andconcentrated. The residue is dissolved in MeOH (50 mL) and K₂CO₃ (7.8 g,60 mmol) is added. The mixture is stirred at room temperature for 5hours and then filtered, concentrated, and purified by silica gel columnchromatography (EA:PE=1:5) to give 115 as a solid (4.0 g, 49% yield).(MS: [M+H]⁺ 270.1).

Step 3: Bronic Ester 116

To a solution of 115 in THF (20 mL) is added CuCl (45 mg, 0.45 mmol),bis(pinacolato)diboron (4.5 g, 18 mmol), Xantphos (1.3 g, 2.25 mmol),potassium tert-butoxide (100 mg, 0.9 mmol) and MeOH (960 mg, 30.0 mmol).After stirring at room temperature for 2 hours, the mixture isconcentrated and purified by silica gel column chromatography(EA:PE=1:3) to give 116 as a white solid (3.5 g, 29%). (MS: [M+H]⁺398.2).

Step 4: BB1

A mixture of 116 (1.9 g 4.78 mmol) and sodium periodate (2.0 g 9.56mmol) in acetone (10 mL) and water (10 mL) is stirred at roomtemperature for 16 hours. The mixture is then diluted with EA (100 mL),washed with water (50 mL×3), dried over anhydrous sodium sulfate,filtered, concentrated, and purified by silica gel column chromatography(EA:PE=1:1) to give BB1 as a white solid (600 mg 40%). (MS: [M+H]⁺316.1)

Preparation of BB2

Step 2: Ketone 117

To a solution of AB1 (280 mg, 1.6 mmol) in acetone (5 mL) is addedactivated manganese(IV) oxide (704 mg, 8.0 mmol). After stirring at roomtemperature for 3 hours, the mixture is filtered, concentrated, andpurified by silica gel column chromatography (EA:PE=1:5) to give 117 asa yellow solid (160 mg, 59%). (MS: [M+H]⁺ 171.0)

Step 3: BB2

To a solution of 117 (120 mg, 0.7 mmol) in carbon tetrachloride (10 mL)is added bromine (0.07 mL, 1.4 mmol) and aluminum chloride (19 mg, 0.14mmol). After stirring at room temperature overnight, the mixture isdiluted with EA, washed with water and brine, dried over anhydroussodium sulfate, filtered, concentrated, and purified by silica gelcolumn chromatography (EA:PE=1:3) to give BB2 as a yellow solid (110 mg,63%). (MS: [M+H]⁺249.1)

Preparation of BB3

Step 1: Ester 119

To a mixture of NaH (2.75 g, 114 mmol) in Et₂O (75 mL) is added asolution of 118 (20 g, 114 mmol) and ethyl formate (10.2 g, 138 mmol) inEtOH (20 mL). After stirring at room temperature overnight, water (50mL) is added and the layers are separated. The aqueous layer isneutralized with 2 M HCl and extracted with ether (50 mL×3). Thecombined organic layers are washed with brine, dried over anhydroussodium sulfate, filtered, and concentrated to give crude 119 (12 g,52%). (MS: [M+H]⁺ 203.1)

Step 2: Pyrimidine 120

To a solution of crude 119 (53.4 g, 0.26 mol) and S-methylisothioureahemisulfate salt (36.8 g, 0.264 mol) in water (240 mL) is added NaOH(15.8 g, 0.40 mol) in water (60 mL). After stirring at 100° C. for 1hour, the mixture is neutralized with acetic acid. The solid iscollected by filtration, washed with water, and dried to give 120 (32.6g, 55% yield). (MS: [M+H]⁺ 229.1)

Step 3: Pyrimidine 121

A mixture of 120 (28.8 g, 0.128 mol) in phosphoryl chloride (240 mL) isstirred under reflux for 4 hours. After cooling to room temperature, themixture is concentrated, co-evaporated with benzene twice, and purifiedby silica gel column chromatography (EA:hexanes=1:3) to give 121 as ayellow oil (29.7 g 94% yield). (MS: [M+H]⁺ 247.1)

Step 4: Pyrimidine 122

To a solution of 121 (2.6 g, 10 mmol) in EtOH (20 mL) is added zincpowder (2.6 g, 40 mmol) and HOAc (2 mL). After stirring at roomtemperature overnight, the mixture is filtered and concentrated. Theresidue is dissolved in EA (30 mL), washed with brine, dried overanhydrous sodium sulfate, filtered, and concentrated to give 122 as ayellow oil (1.2 g, 56% yield). (MS: [M+H]⁺ 213.1)

Step 5: Pyrimidine 123

To a mixture of 122 (500 mg 2.44 mmol) and NaH (142 mg 3.6 mmol) in DMF(5 mL) is added 1,2-dibromoethane (900 mg 4.8 mmol). After stirring atroom temperature overnight, the mixture is diluted with EA (10 mL),washed with brine, dried over anhydrous sodium sulfate, filtered,concentrated, and purified by silica gel column chromatography(EA:PE=1:5) to give 123 as a yellow oil (240 mg, 41%). (MS: [M+H]⁺239.1)

Step 7: alcohol 124

Prepared by using Procedure D.

Step 7: BB3

Prepared by essentially the same method as for B20. (MS: [M+H]⁺ 275.1)

Preparation of BB4

Step 1: Alcohol A50-d₁

Prepared by essentially the same method as for A50 using 48, sodiumborodeuteride, THF, and MeOD. (MS: [M+H]⁺ 341.2)

Step 3: BB4

Following Procedure G using A50-di (80 mg, 0.23 mmol), DCM (5 mL) andthionyl chloride (55 mg, 0.47 mmol) gives crude BB4 (60 mg, 100%). (MS:[M+H]⁺ 259.1)

Preparation of BB5

Step 1: Dibromide 126

To a mixture of 125 (2.0 g, 13.02 mmol) in t-butanol (100 mL) is addedpyridinium tribromide (25.0 g 78.1 mmol). After stirring at roomtemperature for 16 hours, the mixture is concentrated and the residue isdissolved in EA (100 mL), washed with brine (50 mL×3), dried overanhydrous sodium sulfate, filtered, concentrated, and purified by silicagel column chromatography (EA:PE=2:1) to give 126 as a solid (3.5 g82%). (MS: [M+H]⁺ 327.8)

Step 2: Chloride 127

To a mixture of 126 (3.5 g, 10.7 mmol) in HOAc (50 mL) is added Zn dust(7.0 g, 107 mmol). After stirring at room temperature for 2 hours, themixture is concentrated and the residue is dissolved in EA (100 mL),washed with saturated sodium bicarbonate aqueous solution (50 mL×3),brine (50 mL×3), dried over anhydrous sodium sulfate, filtered,concentrated, and purified by silica gel column chromatography(EA:PE=1:2) to give 127 as a solid (1.3 g, 72%). (MS: [M+H]⁺ 170.0)

Step 3: Amine 128

To a mixture of 127 (600 mg, 3.54 mmol) and 2,4-dimethoxybenzylamine(887 mg, 5.31 mmol) in n-butanol (10 mL) is added TEA (716 mg, 7.08mmol). After stirring at 130° C. for 30 minutes under microwaveirradiation, the mixture is concentrated and purified by silica gelcolumn chromatography (EA:PE=1:1) to give 128 as a white solid (700 mg,66%). (MS: [M+H]⁺ 301.1)

Step 4: Ester 129

To a solution of 128 (700 mg, 2.33 mmol) in EtOH (10 mL) is addedconcentrated H₂SO₄ (0.5 mL). After stirring at 80° C. for 30 minutes,the mixture is diluted with EA (100 mL), neutralized with saturatedsodium bicarbonate aqueous solution, washed with brine (30 mL×3), driedover sodium sulfate, filtered, and concentrated to give crude 129 (280mg, 61% yield). (MS: [M+H]⁺ 301.1)

Step 5: Alcohol 130

Prepared by using Procedure E.

Step 6: Carbamate 131

Prepared by essentially the same method as for 74.

Step 7: Alcohol 132

Prepared by essentially the same method as for 75.

Step 8: BB5

Prepared by using the method essentially the same as for B20. (MS:[M+H]⁺333.1)

Preparation of BA5-d₂

Step 1: Acid 133

To a solution of 112 (1.0 g, 5 mmol) in MeOH (15 mL) is added IN NaOHsolution (6 mL). After stirring at room temperature for 1 hour, themixture is concentrated and concentrated HCl (0.5 mL) is added. Thesolid is collected by filtration, washed with water, and dry to give 133as a yellow solid (811 mg, 95%). (MS: [M+H]⁺ 171.1)

Step 2: Alcohol 113-d₂

Following the procedure for A38 using 133 (1.18 g 6.9 mmol), NMM (695mg, 6.9 mmol), THF (20 mL), isobutyl chloroformate (1.13 g, 8.25 mmol),sodium borodeuteride (289 mg, 6.9 mmol), and deueterate water (0.5 mL),then purify with silica gel column chromatography (EA:PE=1:5) to give113-d₂ as a light yellow solid (290 mg, 25%). (MS: [M+H]⁺ 159.1)

Step 3: BA5-d₂

Prepared by essentially the same method as for A50. (MS: [M+H]⁺ 177.1)

Preparation of BB6

Step 1: Aldehyde 134

Prepared by essentially the same method as for 8. (MS: [M+H]⁺ 155.0).

Step 1: Alcohol 135

Prepared by essentially the same method as for AA2.

Step 1: Ketone 136

Prepared by essentially the same method as for 8.

Step 1: BB6

Prepared by essentially the same method as for BB2. (MS: [M+H]⁺ 261.0)

Preparation of BB7

Step 1: Bromide 137

To a mixture of 113 (1.02 g, 6.53 mmol) and PPh₃ (3.4 g, 13.1 mmol) inDCM (50 mL) is added carbon tetrabromide (4.3 g, 13.1 mmol). Afterstirring at room temperature for 16 hours, the mixture is diluted withDCM, washed with brine, dried over anhydrous sodium sulfate, filtered,concentrated, and purified by silica gel column chromatography(EA:PE=1:20) to give 137 as a pale yellow oil (900 mg, 63%). (MS: [M+H]⁺219.0)

Step 2: BB7

A mixture of 137 (255 mg, 1.16 mmol) and PPh₃ (457 mg, 1.75 mmol) intoluene (15 mL) is stirred at 110° C. for 16 hours. The mixture is thencooled and filtered to give BB7 as a white solid (476 mg, 44%). (MS:[M-Br]⁺ 401.1)

The following compounds are prepared by essentially the same method asfor BB7.

Intermediate Structure MS BB8

[M + H]⁺ 528.1

Preparation of C

Preparation of C1

Step 1: Acetate 139

To a solution of 138 (50.0 g, 329 mmol) in DCM (250 mL) is added aceticanhydride (37.5 mL, 399 mmol) and Py (32 mL, 79 mmol). After stirring atroom temperature for 18 hours, water (100 mL) is added and the mixtureis extracted with EA (100 mL×3). The combined organic layers are washedwith 1 N HCl solution (100 mL) and saturated aqueous sodium bicarbonatesolution (100 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated to give crude 139 (60.0 g, 94% yield). (MS: [M+H]⁺ 195.2)

Step 2: Bromide 140

To a suspension of 139 (5.0 g, 25.5 mmol) and potassium bromide (10.0 g,85 mmol) in water (50 mL) is added bromine (1.5 mL, 28.5 mmol) dropwiseat 0° C. After stirring at room temperature for 15 hours, the solid iscollected by filtration, washed with water, and dried to give crude 140as a white solid (6.0 g, 87% yield). (MS: [M+H]⁺ 274.1)

Step 3: C1

A mixture of 140 (66 g, 243 mmol) in 6 N HCl aqueous solution (1.0 L) isstirred at 90° C. for 10 hours and then cooled to room temperature. Thesolid is collected by filtration, washed with water, and dried to giveC₁ as a white solid (50 g, 90% yield). (MS: [M+H]⁺ 232.2)

The following compound is prepared by essentially the same method as forC1.

Intermediate Structure MS C2

[M + H]⁺ 248.9Preparation of C3

Step 1: Catechol 142

To a solution of 141 (30 g, 130 mmol) in DCM (500 mL) is added borontribromide (65.3 g, 261 mmol) dropwise at 0° C. After stirring at roomtemperature for 16 hours, MeOH (100 mL) is added and the mixture isconcentrated and purified by silica gel column chromatography(MeOH:DCM=1:15) to give 142 as a solid (12 g 42% yield). (MS: [M+H]⁺218.2)

Step 2 C3

To a suspension of 142 (4.32 g, 20 mmol) and potassium carbonate (4.14g, 30 mmol) in acetone (20 mL) is added MOMCl (1.7 g, 22 mmol) dropwiseat room temperature. After stirring at room temperature for 12 hours,saturated aqueous ammonium chloride solution (20 mL) is added and themixture is extracted with EA (50 mL×3). The combined organic layers aredried over anhydrous sodium sulfate, filtered, concentrated, andpurified by silica gel column chromatography (EA:PE=1:4) to give C3 asan oil (2.2 g, 42% yield). (MS: [M+H]⁺ 262.2)

Preparation of C4

Step 1: Phenol 144

To a solution of 143 (100 g, 794 mmol) in THF (800 mL) is added n-BuLi(2.5 M in THF, 300 mL, 7.5 mol) at −78° C. dropwise over 1 hour. Afterstirring for 2 hours, trimethyl borate (90 mL, 807 mmol) in THF (200 mL)is added dropwise over 1 hour and the mixture is stirred at −78° C. for30 minutes before HCl solution (2 N, 1.0 L) and 30% hydrogen peroxide(100 mL, 880 mmol) is added at 0° C. After stirring at room temperatureovernight, saturated sodium thiosulfate solution (200 mL) is added andthe mixture is extracted with MTBE (800 mL×2). The combined organiclayers are washed with water (300 mL×2), dried over anhydrous magnesiumsulfate, filtered, and concentrated to give 144 (54.9 g 49% yield). (MS:[M+H]⁺ 143.1)

Step 2: Amine 145

To a solution of 144 (54.9 g, 387 mmol) in EtOH (400 mL) is addedmethylamine aqueous solution (40 wt. %, 82.4 g, 767 mmol) andformaldehyde aqueous solution (37 wt. %, 49 mL, 767 mmol). Afterstirring at reflux for 2 hours, the mixture is cooled to roomtemperature and concentrated. The residue is triturated with ether (200mL) and the solid is collected by filteration give 145 as a white solid(73.0 g, 95% yield). (MS: [M+H]⁺ 200.2)

Step 3: Ammonium Salt 146

To a solution of 145 (73.0 g, 380 mmol) in chloroform (900 mL) is addedMeI (380 mL). After stirring at room temperature overnight, the solid iscollected by filtration to give crude 146 as an off-white solid (124 g,95% yield).

Step 4: Aldehyde 147

To a solution of 146 (124 g, 362 mmol) in HOAc (300 mL) and water (300mL) is added HMTA (196 g, 1.4 mol) under reflux. After stirring for 2hour, concentrated HCl solution (80 mL) is added and the mixture isstirred for 5 minutes, cooled, and extracted with MTBE (800 mL×3). Thecombined organic layers are washed with water (800 mL×2), dried overanhydrous magnesium sulfate, and concentrated to give 147 as a whitesolid (46 g, 75% yield).

Step 5: Pivalate 148

To a solution of 147 (46 g, 271 mmol), TEA (90 mL, 649 mmol), and DMAP(1.65 g, 13.5 mmol) in DCM (500 mL) is added pivaloyl chloride (39 mL,325 mmol) at 0° C. After stirring at room temperature for 2 hours, themixture is diluted with DCM (200 mL), washed with water (100 mL×3),dried over anhydrous magnesium sulfate, filtered, concentrated, andpurified by silica gel column chromatography (EA:PE=1:20) to give 148 asa yellow solid (62 g 91% yield). (MS: [M+H]⁺ 254.1)

Step 6: Bromide 149

Following the procedure for 140 using 148 (10.0 g, 39.4 mmol), potassiumbromide (32.7 g, 275 mmol), water (100 mL), and bromine (12 mL, 236mmol) gives crude 149 as a yellow solid (26.3 g, 99% yield). (MS: [M+H]⁺334.1)

Step 7: C4

To a solution of 149 (333 mg, 1 mmol) in EtOH (5 mL) is added NaOHaqueous solution (4 N, 1 mL, 4 mmol). After stirring at refluxovernight, the mixture is cooled to room temperature, acidified with 6 NHCl aqueous solution to pH 5, and extracted with DCM (20 mL×3). Thecombined organic layers are dried over anhydrous sodium sulfate,filtered, and concentrated to give crude C4 as a yellow solid (195 mg,78% yield). (MS: [M+H]⁺ 249.0)

Preparation of C5

Prepared by essentially the same method as for C3 to give C5 (MS:[M+H]⁺280.2)

Preparation of C6

Step 1: Nitroarene 152

To a suspension 151 (2.5 g, 12.5 mmol) in DCE (20 mL) is added bismuthnitrate pentahydrate (7.28 g, 15 mmol) at room temperature. Afterstirring at 80° C. overnight, the mixture is cooled to room temperature,filtered, concentrated, and purified by silica gel column chromatography(EA:PE=1:10) to give 152 as a light yellow solid (1.19 g, 39% yield).(MS: [M+H]⁺ 246.0)

Step 2: Aniline 153

To a suspension of 152 (1.19 g, 4.86 mmol) and iron powder (0.82 g 14.6mmol) in water (1.2 mL) is added HOAc (2.8 mL) at room temperature.After stirring at 100° C. for 4 hours, the mixture is cooled to roomtemperature and concentrated. Aqueous potassium hydroxide solution (10%,20 mL) is then added and the mixture is filtered, extracted with EA (10mL×3). The combined organic layers are washed with water and brine,dried over anhydrous sodium sulfate, filtered, concentrated, andpurified by silica gel column chromatography (EA:PE=1:10) to give 153 asa white solid (0.63 g, 60% yield). (MS: [M+H]⁺ 216.0)

Step 3: C6

To a solution of 153 (0.63 g, 2.92 mmol) in MeOH (24 mL), THF (1.5 mL),and water (6.0 mL) is added DDQ (1.99 g, 8.77 mmol) at 0° C. Afterstirring at room temperature for 15 minutes, the mixture is extractedwith EA (20 mL×3). The combined organic layers are washed with saturatedaqueous sodium bicarbonate solution and brine, dried over anhydroussodium sulfate, filtered, concentrated, and purified by silica gelcolumn chromatography (EA:PE=1:5) to give C6 as a brown solid (390 mg,58% yield). (MS: [M+H]⁺ 230.0)

Preparation of C7

To a solution of 142 (217 mg, 1 mmol) in DMF (8 mL) is added NaH (120mg, 3 mmol) at 0° C. and stirred at 25° C. for 30 minutes before4-(bromomethyl)pyridine hydrochloride (252 mg, 1 mmol) is added at 0° C.After stirring at 25° C. overnight MeOH (1 mL) is added at 0° C. and themixture is concentrated and purified by silica gel column chromatography(MeOH:DCM=1:50) to give C7 as a yellow solid (100 mg, 35% yield). (MS:[M+H]⁺ 308.1)

Preparation of C8

Step 1: Aldehyde 154

To a solution of A43 (200 mg, 0.87 mmol) in THF (3 mL) is added C3 (190mg 0.73 mmol), PPh₃ (455 mg 1.74 mmol), and DIAD (351 mg 1.74 mmol) atroom temperature. After stirring at 30° C. overnight, the mixture isconcentrated and purified by silica gel column chromatography(MeOH:DCM=1:50) to give 154 as a yellow solid (100 mg, 29% yield). (MS:[M+H]⁺ 473.1)

Step 2: C8

To a solution of 154 (50 mg 0.11 mmol) in DCM (4 mL) is added TFA (0.4mL) dropwise at 0° C. After stirring at room temperature for 20 minutes,the mixture is basified with a saturated aqueous sodium bicarbonatesolution. The solid is collected by filtration, washed with water (3mL), and dried to crude C8 as a yellow solid (23 mg, 50% yield). (MS:[M+H]⁺ 429.0)

The following compounds are prepared by essentially the same method asfor C8.

Intermediate Structure MS C9

[M + H]⁺ 428.0 C10

[M + H]⁺ 428.0Preparation of C11

A solution of 155 (52 mg, 0.2 mmol), HMTA (56 mg, 0.4 mmol) and TFA (1ml) is stirred at 70° C. for 3 hours. The mixture is then concentratedand the residue is dissolved in EA (10 mL), washed with saturatedaqueous sodium carbonate solution (10 mL), dried over anhydrous sodiumsulfate, filtered, concentrated, and purified by silica gel columnchromatography (DCM) to give C11 as a yellow solid (10 mg, 17% yield).(MS: [M+H]⁺286.3)

Preparation of C12

Step 1: Alcohol 157

Following Procedure C using 156 (2.0 g, 9.3 mmol), MeOH (10 mL) andsodium borohydride (0.2 g, 5.3 mmol), dilute the reaction mixture withEA (50 mL), wash with water (50 mL) and brine (20 mL), dry overanhydrous sodium sulfate, filter, and concentrate to give 157 as ayellow solid (2 g, 100% yield). (MS: [M+H]⁺ 215.1)

Step 2: Phenol 158

A solution of 157 (0.5 g, 2.3 mmol), DCM (5 mL), triethylsilane (0.7 mL,4.6 mmol), and TFA (1 mL) is stirred at room temperature overnight andthen concentrated and purified by silica gel column chromatography(EA:PE=1:10) to give 158 as a yellow oil (0.3 g, 60% yield). (MS: [M+H]⁺201.2)

Step 3: C12

A solution of 158 (0.1 g 0.5 mmol), TFA (3 mL), and HMTA (0.14 g, 1.0mmol) is stirred at 105° C. for 30 minutes and then diluted with EA (100mL), washed with saturated sodium bicarbonate (20 mL×2), dried overanhydrous sodium sulfate, filtered, concentrated, and purified by silicagel column chromatography (EA:PE=1:10) to give C12 as a yellow oil (30mg, 30% yield). (MS: [M+H]⁺ 229.2)

Preparation of C13

Step 1: Ketone 160

A mixture of 159 (5.0 g, 26.7 mmol) and acetyl chloride (10.5 g, 134mmol) is stirred at 60° C. for 1 hour before aluminum chloride (5.4 g,40.1 mmol) is added at room temperature. After stirring at 160° C. for 2hours, the mixture is cooled to room temperature, poured into saturatedammonium chloride solution (50 mL), and extracted with EA (50 mL×5). Thecombined organic layers are dried over anhydrous sodium sulfate,filtered, and concentrated to crude 160 as an off-white solid (5.5 g,90% yield). (MS: [M+H]⁺ 229.0)

Step 2: Acetate 161

To a solution of 160 (3.0 g, 13.1 mmol) and TEA (2.6 g, 26.2 mmol) inDCM (30 mL) is added acetyl chloride (1.54 g 19.6 mmol) dropwise at roomtemperature. After stirring for 1 hour, the mixture is poured into asaturated ammonium chloride solution (20 mL) and extracted with EA (50mL×5). The combined organic layers are dried over anhydrous sodiumsulfate, filtered, concentrated, and purified by silica gel columnchromatography (EA:PE=1:10) to give 161 as an off-white solid (3.3 g,93% yield).

Step 3: Bromide 162

To a solution of 161 (2.0 g, 7.4 mmol) in carbon tetrachloride (15 mL)is added NBS (2.6 g, 14.7 mmol) and AIBN (200 mg, 1.2 mmol). Afterstirring at 90° C. for 16 hours, the mixture is cooled, concentrated,and purified by silica gel column chromatography (EA:PE=1:10) to give162 as an off-white solid (3.0 g, 94% yield).

Step 4: C13

To a solution of 162 (3.0 g, 6.9 mmol) in EtOH (30 mL) is added asolution of silver nitrate (5.9 g, 34.9 mmol) in water (20 mL) dropwise.After stirring at 75° C. for 16 hours, the mixture is extracted with EA(20 mL×3). The combined organic layers are dried over anhydrous sodiumsulfate, filtered, concentrated, and purified by silica gel columnchromatography (EA:PE=1:8) to give C13 as an off-white solid (1.6 g 94%yield). (MS: [M+H]⁺ 243.0)

Preparation of C14

To a solution of 163 (230 mg, 1.0 mmol) and Py (0.25 ml, 3.1 mmol) inDCM (5 mL) is added trifluoromethanesulfonic anhydride (338 mg, 1.2mmol) dropwise at 0° C. After stirring at room temperature overnight,the mixture is concentrated and purified by prep-TLC (MeOH:DCM=1:20) togive C14 as a yellow solid (303 mg, 84% yield). (MS: [M+H]⁺ 362.0)

Preparation of C15

Step 1: Sulfonyl Chloride 165

To chlorosulfonic acid (4.1 g, 35.2 mmol) is added 164 (1.0 g 7.04 mmol)in portions. After stirring at 100° C. for 16 hours, the mixture iscooled to room temperature, poured into ice water (100 mL), andextracted with EA (50 mL×2). The combined organic layers are washed withbrine (100 mL), dried over anhydrous sodium sulfate, filtered,concentrated, and purified by silica gel column chromatography(EA:PE=1:5) to give 165 as a yellow solid (100 mg, 6% yield). (MS:[M+H]⁺ 241.0)

Step 2: Alcohol 166

Following Procedure C using 163 (671 mg, 2.92 mmol), MeOH (3 mL), andsodium borohydride (220 mg, 5.84 mmol), workup with saturated aqueoussodium bicarbonate solution (3 mL) and water (5 mL), extract with EA (30mL×3), wash the combined organic layers with brine (100 mL), dry overanhydrous sodium sulfate, filter, concentrate, and purify with silicagel column chromatography (EA:PE=1:3 to 1:2) give 166 as a pale yellowsolid (550 mg, 81% yield). (MS: [M+H]⁺ 232.0)

Step 3: Sulfonamide 167

To a solution of 165 (100 mg 0.41 mmol) in Py (2 mL) is added 166 (230mg, 1.0 mmol). After stirring at room temperature for 16 hours, themixture is acidified with 1 N HCl solution to pH 7 and extracted with EA(30 mL×3). The combined organic layers are washed with brine (100 mL),dried over anhydrous sodium sulfate, filtered, and concentrated to give167 as a yellow solid (130 mg, 72% yield). (MS: [M+H]⁺ 436.0)

Step 4: Alcohol 168

To a solution of 167 (130 mg, 0.30 mmol) in EtOH (2 mL) is added HCl (4M in 1,4-dioxane, 2 mL, 8.0 mmol) at room temperature. After stirring at80° C. for 2 hours, the mixture is cooled to room temperature, basifiedwith 1 N aqueous NaOH solution to pH 9, and extracted with EA (50 mL×3).The combined organic layers are washed with brine (100 mL), dried overanhydrous sodium sulfate, filtered, concentrated, and purified by silicagel column chromatography (MeOH:DCM=1:50) to give 168 as a pale yellowsolid (100 mg, 85% yield). (MS: [M+H]⁺ 394.0)

Step 5: C15

To a solution of 168 (100 mg, 0.25 mmol) in DMF (2 mL) and DCM (5 mL) isadded activated manganese(IV) oxide (376 mg, 4.33 mmol). After stirringat room temperature for 2 hours, the mixture is filtered through a padof Celite and concentrated to give C15 as a yellow solid (80 mg, 81%yield). (MS: [M+H]⁺ 392.0)

Preparation of C16

Step 1: Phenol 169

To a solution of 152 (2.5 g, 10.2 mmol) in DCM (30 mL) is added borontribromide (3.0 mL, 30.5 mmol) dropwise at −78° C. After stirring atroom temperature overnight, MeOH (2 mL) is added at 0° C. and themixture is extracted with DCM (20 mL×3). The combined organic layers aredried over anhydrous sodium sulfate, filtered, concentrated, andpurified by silica gel column chromatography (MeOH:DCM=1:100) to give169 as a yellow solid (2.3 g, 98% yield). (MS: [M+H]⁺ 233.0)

Step 2: Benzyl Ether 170

To a solution of 169 (2.3 g, 9.91 mmol) in DMF (20 mL) is addedpotassium carbonate (4.11 g, 29.7 mmol) and benzyl bromide (1.4 mL, 11.9mmol). After stirring at 80° C. overnight, the mixture is cooled to roomtemperature followed by addition of EA (40 mL) and water (20 mL). Thelayers are separated and the aqueous layer is extracted with EA (40mL×3). The combined organic layers are washed with saturated ammoniumchloride aqueous solution, dried over anhydrous sodium sulfate,filtered, concentrated, and purified by silica gel column chromatography(MeOH:DCM=1:100) to give 170 as a yellow solid (2.7 g, 85% yield). (MS:[M+H]⁺ 323.2)

Step 3: Aniline 171

To a mixture of 170 (1.7 g, 5.28 mmol) in saturated ammonium chlorideaqueous solution (4 mL) and EtOH (20 mL) is added iron powder (1.8 g,31.66 mmol). After stirring at 90° C. overnight, the mixture isfiltered, and extracted with EA (40 mL×3). The combined organic layersare dried over anhydrous sodium sulfate, filtered, concentrated, andpurified by silica gel column chromatography (MeOH:DCM=1:100) to give171 as a white solid (1.1 g, 71% yield). (MS: [M+H]⁺ 293.2)

Step 4: Aldehyde 172

To a solution of 171 (1.1 g, 3.76 mmol) in THF (25 mL), MeOH (5 mL), andwater (1 mL) is added DDQ (2.6 g 11.3 mmol) at 0° C. After stirring atroom temperature for 30 minutes, the mixture is extracted with EA (30mL×3). The combined organic layers are washed with brine, dried overanhydrous sodium sulfate, filtered, concentrated, and purified by silicagel column chromatography (EA:PE=1:10) to give 172 as a brown solid (1.1g, 95% yield). (MS: [M+H]⁺ 307.2)

Step 5: C16

To a solution of 172 (700 mg 2.29 mmol) and Py (0.7 mL, 9.15 mmol) inDCM (10 mL) is added 165 (660 mg 2.74 mmol) at 0° C. After stirring atroom temperature overnight, the mixture is concentrated and purified bysilica gel column chromatography (MeOH:DCM=1:100) to give C16 as a greysolid (430 mg 37% yield). (MS: [M+H]⁺ 511.4)

Preparation of C17

To a solution of 173 (1.0 g, 7.2 mmol) in DCM (20 mL) is added TiCl₄solution (1M, 15 mL, 15.0 mmol) at −78° C. After stirring for 10minutes, dichloromethyl methyl ether (1.1 mL, 12.2 mmol) is added andthe mixture is stirred at room temperature for 4 hours. The mixture isthen poured onto ice and the solid is collected by filtration, washedwith EA and ether, and dried to give crude C17 as a brown powder (131mg, 11% yield).

Preparation of C18

Step 1: Indoline 175

To a mixture of 174 (5.0 g, 25.5 mmol) in HOAc (10 mx) is added sodiumcyanoborohydride (4.8 g, 76.5 mmol) at 0° C. After stirring at roomtemperature for 2 hours, the mixture is poured into saturated sodiumbicarbonate solution (100 mL) slowly and extracted with EA (50 mL×6).The combined organic layers are dried over anhydrous sodium sulfate,filtered, concentrated, and purified by silica gel column chromatography(EA:PE=1:10) to give 175 as a white solid (3.5 g 69% yield). (MS: [M+H]⁺198.0)

Step 2: Indoline 176

To a mixture of 175 (8801.2 g, 4.4 mmol) in DMF (10 methoxybenzylchloride (835 m 5.3 mmol) in DMF (8 mL) is added potassium carbonate(920 mg, 6.6 mmol) and sodium iodide (88 mg, 0.6 mmol). After stirringat 50° C. for 16 hours, the mixture is poured into saturated ammoniumchloride solution (20 mL), and extracted with EA (50 mL×3). The combinedorganic layers are dried over anhydrous sodium sulfate, filtered,concentrated, and purified by silica gel column chromatography(EA:PE=1:30) to give 176 as a colorless oil (1.2 g 85% yield). (MS:[M+H]⁺ 318.0)

Step 3: Aldehyde 177

To a mixture of 176 (1.2 g 3.8 mmol) in DMF (10 mL) is added phosphorylchloride (867 mg, 5.7 mmol) dropwise at 0° C. After stirring at roomtemperature for 1 hour and at 50° C. for 1 hour, the mixture is pouredinto saturated ammonium chloride solution (30 mL) and extracted with EA(50 mL×3). The combined organic layers are dried over anhydrous sodiumsulfate, filtered, concentrated, and purified by silica gel columnchromatography (EA:PE=1:10) to give 177 as a light yellow oil (1.2 g,91% yield). (MS: [M+H]⁺ 346.0)

Step 4: indoline 178

To a solution of 177 (1.0 g, 2.9 mmol) in DCM (5 mL) is added TFA (10mL). After stirring at room temperature for 16 hours, the mixture isconcentrated and purified by silica gel column chromatography(EA:PE=1:10) to give 178 as an off-white solid (600 mg, 92% yield). (MS:[M+H]⁺ 226.0)

Step 5: C18

To a solution of 178 (800 mg, 3.5 mmol) in DCM (8 mL) is added activatedmanganese(IV) oxide (1.2 g, 14.1 mmol). After stirring at roomtemperature for 16 hours, the mixture is filtered and concentrated togive crude C18 as a white solid (700 mg, 87% yield). (MS: [M+H]⁺ 224.0)

Preparation of C19

To a solution of C5 (100 mg, 0.36 mmol) in DMF (5 mL) is added B15 (100mg, 0.43 mmol) and potassium carbonate (99.4 mg, 0.72 mmol). Afterstirring at 50° C. for 2 hours, the mixture is diluted with EA (10 mL),washed with aqueous lithium chloride solution (10 mL×3), dried overanhydrous sodium sulfate, fitered, concentrated, and purified by silicagel column chromatography (MeOH:DCM=1:50) to give C19 as a white solid(120 mg, 86% yield). (MS: [M+H]⁺ 487.3)

The following compounds are prepared by essentially the same method asfor C19 from B26, B27, B28, and B29, respectively, with an option ofremoving MOMO group using essentially the same method as for C8.

Inter- mediate Structure MS C20

[M + H]⁺ 349.0 C21

[M + H]⁺ 349.9 C22

[M + H]⁺ 533.9 C23

[M + H]⁺ 446.8Preparation of C24

Step 1: Ketone 180

To a solution of 179 (260 mg, 1.5 mmol) in DMF (4 mL) is addedtributyl(1-ethoxyvinyl)tin (543 mg, 1.5 mmol) and Pd(dppf)Cl₂ (110 mg,0.15 mmol). After stirring at 100° C. for 16 hours, the mixture iscooled to room temperature, filtered, concentrated, and purified bysilica gel column chromatography (MeOH:DCM=1:50) to give 180 as a brownsolid (30 mg, 15% yield). (MS: [M+H]⁺ 138.1)

Step 2: Alcohol 181

Following Procedure C using 180 (137 mg, 1.0 mmol), MeOH, and sodiumborohydride (19 mg 0.5 mmol), purify with silica gel columnchromatography (MeOH:DCM=1:30) to give 181 as a white solid (100 mg, 73%yield). (MS: [M+H]⁺ 140.2)

Step 3: C24

To a mixture of C3 (130 mg, 0.5 mmol), 181 (70 mg, 0.5 mmol), and PPh₃(262 mg, 1.0 mmol) in THF is added DIAD (200 mg, 1.0 mmol) at roomtemperature. After stirring at room temperature for 30 minutes, themixture is concentrated and purified by silica gel column chromatography(MeOH:DCM=1:30) to give C24 as a white solid (60 mg, 32% yield). (MS:[M+H]⁺ 383.3)

Preparation of C25

A mixture of 182 (113 mg, 0.44 mmol), C1 (50 mg, 0.22 mmol) and cesiumcarbonate (143 mg, 0.44 mmol) in MeCN (2 mL) is stirred at 70° C. for1.5 hours. The mixture is then cooled to room temperature, diluted withDCM (10 mL), washed with water (10 mL×3), dried over anhydrous sodiumsulfate, and concentrated to give crude C25 as a brown solid (80 mg, 56%yield). (MS: [M+H]⁺ 330.1)

Preparation of C26

Step 1: Acid 184

To a solution of 183 (25 g, 114 mmol) in sulfuric acid (228 mL) is addedpotassium nitrate (11.5 g 114 mmol) at 0° C. over 10 minutes. Afterstirring at room temperature for 3 hours, the mixture is poured onto iceand the solid is collected by filtration, washed with water, dried, andpurified by prep-HPLC (water/MeOH with 0.1% TFA, 35% to 60%) to give 184as a white solid (5.6 g, 52% yield). (MS: [M+H]⁺ 265.2)

Step 2: Ester 185

To a solution of 184 (5.5 g, 20.9 mmol) in MeOH (50 mL) is added thionylchloride (5 g, 42 mmol) dropwise at 0° C. After stirring at 120° C. for4 hours, the mixture is concentrated and purified by silica gel columnchromatography (EA:PE=1:4) to give 185 as a white solid (4.0 g, 70%yield). (MS: [M+H]⁺ 279.1)

Step 3: Aniline 186

A mixture of 185 (55 mg, 0.2 mmol), tert-butylamine (29.2 mg, 0.4 mmol),and Py (1 mL) is stirred at room temperature for 18 hours. The mixtureis then diluted with EA (20 mL), washed with IN HCl solution (5 mL),dried over anhydrous sodium sulfate, and concentrated to give crude 186as a yellow solid (30 mg, 45% yield). (MS: [M+H]⁺ 332.1)

Step 4: Aniline 187

To a solution of crude 186 (4.0 g 12.1 mmol) in MeOH (20 mL) is addedconcentrated sulfuric acid (1 mL) at 0° C. After stirring at 100° C. for16 hours, the mixture is diluted with saturated aqueous sodiumbicarbonate solution (20 mL) and extracted with EA (50 mL×3). Thecombined organic layers are dried over anhydrous sodium sulfate,filtered, and concentrated to give crude 187 as a brown solid (3.0 g,91% yield). (MS: [M+H]⁺ 276.2)

Step 5: Ester 188

A mixture of 187 (3.0 g, 11 mmol), iron powder (3.0 g, 55 mmol),saturated aqueous ammonium chloride solution (10 mL), and EtOH (10 mL)is stirred at 80° C. for 1.5 hours. The mixture is then filtered,diluted with water and extracted with EA (50 mL×3). The combined organiclayers are dried over anhydrous sodium sulfate, filtered, andconcentrated to give crude 188 as a brown solid (2.4 g 92% yield). (MS:[M+H]⁺ 246.1)

Step 6: Benzotriazole 189

To a solution of crude 188 (2.0 g 8.20 mmol) in MeOH is added 1 N HCl(120 mL) and sodium nitrite (622 mg, 9.0 mmol) at 0° C. After stirringat room temperature for 1 hour, saturated aqueous sodium bicarbonatesolution (50 mL) is added and the mixture is extracted with EA (100mL×3). The combined organic layers are dried over anhydrous sodiumsulfate, filtered, and concentrated to give crude 189 as a brown solid(1.5 g, 83% yield). (MS: [M+H]⁺ 256.2)

Step 7: alcohol 190

Following Procedure E using 189 (1.0 g, 3.92 mmol), THF (10 mL), and LAH(300 mg, 8.0 mmol), quench the reaction with water (10 mL), acidify themixture with 6 N HCl solution to pH 3, extract with THF (30 mL×3), drythe combined organic layers over anhydrous sodium sulfate, filter, andconcentrate to give crude 190 as a brown solid (700 mg, 79% yield). (MS:[M+H]⁺ 229.1)

Step 8: C26

A mixture of 190 (700 mg, 3.08 mmol), PDC (1.27 g, 3.39 mmol) in acetone(20 mL) is stirred at room temperature for 4 hours. The mixture is thenconcentrated and purified by silica gel column chromatography(EA:PE=1:2) to give C26 as a gray solid (200 mg, 29% yield). (MS: [M+H]⁺227.2)

Preparation of C27

Prepared by essentially the same methods as for C8 to give C27 as anoff-white solid. (MS: [M+H]⁺ 323.9)

Preparation of C28

Step 1: Catechol 193

To a solution of 192 (322 mg, 1.75 mmol) in DCM (2 mL) is added borontribromide (1 M in DCM, 4 mL, 4 mmol) at 0° C. After stirring at roomtemperature for 2 hours, water (0.5 mL) is added. The organic layer iswashed with water (2 mL) and brine (2 mL), dried over anhydrous sodiumsulfate, and concentrated to give crude 193 (280 mg, 99% yield).

Step 2: Phenol 194

To a mixture of crude 193 (34 mg) and potassium carbonate (45 mg, 0.33mmol) in acetone (2 mL) is added benzyl bromide (0.03 mL, 0.24 mmol).After stirring overnight, water (1 mL) and EA (10 mL) are added. Thelayers are separated and the organic layer is washed with water (2 mL)and brine (2 mL), dried over anhydrous sodium sulfate, concentrated, andpurified by silica gel column chromatography (EA:hexanes=1:3) to give194 as white solid (30 mg, 55% yield).

Step 3: Methyl Ether 195

To a mixture of 194 (13 mg, 0.05 mmol) and potassium carbonate (11 mg,0.08 mmol) in acetone (1.5 mL) is added dimethyl sulfate (0.015 mL, 0.16mmol). After stirring at reflux for 2 hours and cooled back to roomtemperature, the mixture is concentrated and then EA (10 mL) is added.The organic layer is washed with 5% ammonium chloride aqueous solution(2 mL), water (5 mL), and brine (5 mL), dried over anhydrous sodiumsulfate, and concentrated to give crude 195 (15 mg, 99% yield).

Step 4: C28

To a solution of 195 (15 mg, 0.058 mmol) in MeOH (1.0 mL) is added Pd/C(20 wt. %, 3 mg). After stirring overnight, the mixture is purified bysilica gel column chromatography (EA/hexanes=1:3) to give C28 as a whitesolid (8 mg, 81% yield). (MS: [M+H]⁺ 171.2).

Preparation of C29

Step 1: Benzyl Ether 196

To a mixture of C1 (230 mg, 1.0 mmol) and potassium carbonate (180 mg,1.3 mmol) in DMF (1.0 mL) is added benzyl bromide (0.125 mL, 1.15 mmol).After stirring at 60° C. for 1.5 hours, the mixture is cooled to roomtemperature and water (2 mL) and EA (10 mL) are added. The layers areseparated and the organic layer is washed by brine (5 mL), dried overanhydrous sodium sulfate, and concentrated to give crude 196 (300 mg,94% yield).

Step 2: Alcohol 197

Following Procedure C using crude 196 (300 mg, 0.94 mmol), THF (1.5 mL),water (0.3 mL), and sodium borohydride (20 mg, 0.54 mmol), dilute thereaction mixture with EA (15 mL), washed with brine (5 mL), dried overanhydrous sodium sulfate, and concentrate to give crude 197 (286 mg, 95%yield).

Step 3: Benzyl Ether 198

To a mixture of NaH (53 mg 1.33 mmol) in THF (1 mL) is added a solutionof 197 (286 mg, 0.89 mmol) at 0° C. After stirring for 30 min, benzylbromide (0.14 mL, 1.15 mmol) is added and the mixture is stirred at roomtemperature overnight. The mixture is then cooled to 0° C. and saturatedammonium chloride solution (1 mL) is added. The mixture is thenextracted with EA (10 mL) and the organic layer is washed with brine (5mL), dried over anhydrous sodium sulfate, concentrated and purified bysilica gel flash chromatography (EA:hexanes=1:10) to give 198 as a whitesolid (330 mg, 91% yield).

Step 4: Trifluoride 199

A mixture of 198 (52 mg, 0.125 mmol), sodium trifluoroacetate (51 mg,0.38 mmol), and CuI (48 mg, 0.25 mmol) in DMF (1 mL) and dimethylacetamide (0.5 mL) is stirred at 152° C. After cooling to roomtemperature, water (2 mL) and EA (15 mL) are added. The organic layer iswashed with brine (5 mL), dried over anhydrous sodium sulfate, andconcentrated to give crude 199 (50 mg).

Step 5: Alcohol 200

A solution of crude 199 (10 mg) and Pd/C (30 wt. %, 1.5 mg) in MeOH (1.0mL) and THF (0.2 mL) is stirred at 50° C. under hydrogen for 2 hours.The mixture is then purified by prep-TLC (EA:hexanes=1:2) to give 200 asa white solid (5 mg, 89% yield for two steps). (MS: [M+H]⁺ 223.0)

Step 6: C29

Following Procedure G using 200 (5 mg, 0.022 mmol), DCM (1.0 mL), DMP(15 mg, 0.045 mmol), and water (0.6 μL, 0.045 mmol), react for 30minutes and then add EA (5 mL), wash with brine (5 mL), dried overanhydrous sodium sulfate, and concentrated to give crude C29 (1.2 mg,24% yield). (MS: [M+H]⁺ 221.1)

Preparation C30

A mixture of NaH (95 mg, 2.4 mmol) in DMSO (1 mL) is stirred for 10minutes before a solution of 142 (235 mg, 1.1 mmol) in DMSO (1 mL) isadded. After stirring for 30 minutes, propargyl bromide (0.13 mL, 1.2mmol) is added dropwise and the mixture is stirred overnight before icewater (0.5 mL) is added at 0° C. The mixture is then extracted with EA(5 mL), and the organic layer is washed with water (1 mL) and brine (1mL), dried over anhydrous sodium sulfate, concentrated, and purified bysilica gel column chromatography (EA:hexanes=1:3) to give C30 as a whitesolid (180 mg, 65% yield). (MS: [M-1]⁻ 253.2)

Preparation of C31

Step 1: Alcohol 202

Follow Procedure C using 201 (3.0 g, 8.8 mmol), MeOH (30 mL), and sodiumborohydride (0.57 g, 15 mmol), quench with saturated ammonium chloride(50 mL) and dilute with EA (200 mL), wash with water (100 mL) and brine(50 mL), dried over anhydrous sodium sulfate, and concentrate to give202 (2.9 g, 99% yield). (MS: [M+H]⁺343.0)

Step 2: Cyanide 203

A mixture of 202 (1.37 g, 4.0 mmol) and CuCN (0.39 g 4.4 mmol) in DMF(10 mL) is stirred at 85° C. overnight. After cooling to roomtemperature, the mixture is diluted with EA (50 mL), filtered, washedwith saturated sodium bicarbonate (50 mL) and brine (50 mL), dried overanhydrous sodium sulfate, concentrated, and purified by silica gel flashchromatography (EA:hexanes=1:3) to give 203 as a white solid (0.57 g,59% yield). (MS: [M+H]⁺ 242.2)

Step 3: Tetrazole 204

A mixture of 203 (0.12 g 0.5 mmol), ammonium chloride (0.11 g 4 mmol)and sodium azide in DMF (2 mL) is stirred at 100° C. overnight. Aftercooling to room temperature, the mixture is diluted with EA (10 mL) and1 N HCl (4 mL). The layers are separated and the organic layer is washedwith water (5 mL) and brine (5 mL), dried over anhydrous sodium sulfate,and concentrated to give crude 204 (96 mg, 67% yield). (MS: [M+H]⁺285.2)

Step 4: C31

Following Procedure G using 204 (29 mg, 0.1 mmol), DCM (1.0 mL), and DMP(64 mg, 0.15 mmol) to give C31 (30 mg, 99% yield). (MS: [M+H]⁺ 283.2)

Preparation of C32

A solution of C1 (200 mg, 0.87 mmol) and(triphenylphosphoranyliden)acetaldehyde (264 mg, 0.87 mmol) in toluene(5 mL) is stirred at 80° C. overnight. The mixture is then concentratedand purified by prep-TLC (EA:hexanes=7:10) to give C32 as a yellow solid(5 mg, 2% yield).

Preparation of C33

To a solution of 205 (100 mg, 0.52 mmol) in THF (2 mL) is added boranetetrahydrofuran complex (1.0 M, 1.57 mL, 1.57 mmol) at 0° C. Afterstirring at room temperature overnight, water (1 mL) is added themixture is diluted with EA (10 mL). The organic layer is washed with 1 NHCl (5 mL) and brine (5 mL×3), dried over anhydrous sodium sulfate, andconcentrated. Next follow Procedure G using half of the residue obtainedabove, DCM (2.0 mL), and DMP (250 mg, 0.6 mmol) to give C32 as a whitesolid (36 mg, 79% yield for two steps). (MS: [M+H]⁺ 176.2).

Preparation of C34

A mixture of 206 (147 mg, 1 mmol) and polyphosphoric acid (2.11 g) inchloroform (0.1 mL) is stirred at 80° C. for 2 hours. After cooling toroom temperature, saturated sodium bicarbonate (200 mL) is added slowlyand the mixture is extracted with EA (300 mL×4). The combined organiclayers are washed with brine (150 mL×3), dried over anhydrous sodiumsulfate, concentrated to give C34 as a yellow solid (75 mg, 42% yield).(MS: [M+H]⁺ 179.2)

Preparation of C35

Step 1: Ester 208

To a solution of 207 (5.0 g 21.6 mmol) in MeOH (50 mL) is added thionylchloride (7.7 g 64.9 mmol, 4.7 mL) at 0° C. After stirring at 80° C. for2 hours, the mixture is concentrated and the residue is dissolved in DCM(200 mL), washed with saturated sodium bicarbonate solution (50 mL×3),dried over anhydrous sodium sulfate, and concentrated to give crude 208as a yellow oil (4.80 g 91% yield).

Step 2: Sulfonyl Chloride 209

To A mixture of 208 (500 mg, 2.04 mmol) and chlorosulfonic acid (1.19 g10.2 mmol, 0.68 mm) is stirred at 60° C. for 12 hours, the mixture isdiluted with DCM (10 mL), washed with water (3 mL×3) and brine (3 mL×3),dried over anhydrous sodium sulfate, concentrated, and purified byprep-TLC (EA:PE=1:3) to provide 209 as a white solid (500 mg, 71%yield).

Step 3: Methyl Sulfide 210

To a solution of 209 (2.0 g, 5.82 mmol) in toluene (20 mo) is added PPh₃(4.58 g 17.5 mmol) in toluene (20 ms) at 0° C. After stirring at 15° C.for 2 hours, TEA (1.77 g, 17.5 mmol, 2.4 mL) and methyl iodide (2.48 g17.5 dried mmol, 1.1 m) are added and the mixture is stirred at 15° C.for another 30 minutes before it is concentrated and purified by silicagel column chromatography (EA:PE=1:10 to 1:5) to give 210 as a whitesolid (1.69 g, 30% yield).

Step 4: Alcohol 211

Following Procedure E using 210 (500 mg, 1.72 mmol), THF (10 mL), andLAH (98 mg, 2.58 mmol), react at −20° C. to give 211 as a white solid(400 mg, 88% yield).

Step 5: Aldehyde 212

Following the procedure for 8 using 211 (350 mg, 1.33 mmol), DCM (5 mL),activated manganese(IV) oxide (1.16 g, 13.3 mmol), react at 15° C. for12 hours to give crude 212 as a yellow solid (320 mg, 92% yield).

Step 6: C35

To a solution of 212 (320 mg, 1.23 mmol) in DCM (5 mL) is added withboron tribromide (308 mg, 1.23 mmol, 0.12 mL) at −40° C. After stirringat 15° C. for 12 hours, MeOH is added and the mixture is washed withsaturated sodium carbonate (20 mL×3). The aqueous solution is adjustedwith 1 N HCl to pH 4-5 and then extracted with DCM (30 mL×3). Thecombined organic layers are dried over anhydrous sodium sulfate andconcentrated to give C35 as a white solid (130 mg, 43% yield).

The following compound is prepared by essentially the same method as forC19.

Intermediate Building blocks Structure MS CA1

[M + H]⁺ 600.1Preparation of CB1

To a solution of C3 (200 mg 1.2 mmol) and 5-quinolinylboronic acid (200mg 1.5 mmol) in DCM (30 mL) is added Cu(OAc)₂ (130 mg 1.03 mmol) and TEA(300 mg 3.11 mmol). After stirring at room temperature under an oxygenatmosphere for 2 hours, the mixture is concentrated and purified bysilica gel column chromatography (EA:PE=1:10 to 1:3) to give CB1 (85 mg,29%) as a colorless oil. (MS: [M+H]⁺ 388.0)

The following compounds are prepared by essentially the same method asfor C36.

Intermediate Structure MS CB2

[M + H]⁺ 388.0 CB3

[M + H]⁺ 414.0 CB4

[M + H]⁺ 393.0 CB5

[M + H]⁺ 414.0Preparation of CB6

Step 1: Phenol 214

To a mixture of 213 (2.0 g, 8.23 mmol) and acetohydroxamic acid (2.47 g,32.9 mmol) in DMSO (10 mL) is added potassium carbonate (5.69 g, 41.2mmol). After stirring at 80° C. for 16 hours, the mixture is diluted EA(150 mL), washed with brine (50 mL×3), dried over anhydrous sodiumsulfate, filtered, concentrated, and purified by silica gel columnchromatography (EA:PE=1:5) to give 214 as a white solid (1.3 g, 66%).(MS: [M+H]⁺ 240.9)

Step 2: CB6

A mixture of 214 (1.3 g, 5.39 mmol), TFA (20 mL) and HMTA (1.51 g, 10.8mmol) is stirred at 70° C. for 30 minutes. The mixture is thenconcentrated and purified by silica gel column chromatography(EA:PE=1:3) to give CB6 as a white solid (1.1 g, 76% yield). (MS: [M+H]⁺268.9)

Preparation of CB7

Step 1: Alcohol 215

To a solution of 156 (1.0 g, 4.65 mmol) in THF (20 mL) is added MeMgBr(1M in THF, 14 mL, 14.0 mmol) at 0° C. After stirring at roomtemperature for 12 hours, water (20 mL) is added and the mixture isextracted with EA (20 mL×3). The combined organic layers are dried overanhydrous sodium sulfate, concentrated and purified by silica gel columnchromatography (EA:PE=1:15) to give 215 as a yellow solid. (1.0 g, 93%).(MS: [M+H]⁺232.8)

Step 2: Phenol 216

To a solution of 215 (1.0 g, 4.32 mmol) in DCM (10 mL) is addedtriethylsilane (1.5 mL, 9.5 mmol) and TFA (2 mL). After stirring at roomtemperature for 12 hours, the mixture is concentrated and purified bysilica gel column chromatography (EA:PE=1:10) to give 216 as an oil (0.9g, 97%). (MS: [M+H]⁺ 216.7)

Step 3: CB7

To a solution of 216 (900 mg, 4.19 mmol) in TFA (30 mL) is added HMTA(1.4 g, 10.3 mmol). After stirring at 70° C. for 2 hours, saturatedsodium bicarbonate aqueous solution (50 mL) is added and the mixture isextracted with EtOAc (100 mL×3). The combined organic layers are dried,concentrated and purified by silica gel column chromatography(EA:PE=1:5) to give CB7 as an oil. (150 mg, 15%). (MS: [M+H]⁺ 243.2)

Preparation of CB8

Step 1: Alcohol 218

To a solution of 217 (214 mg, 1.0 mmol) in THF is addedtrimethyl(trifluoromethyl)silane (170 mg, 1.2 mmol) at 0° C. followed byTBAF (107 mg, 0.41 mmol). After stirring at room temperature for 1 hour,water is added and the mixture is extracted with EA (20 mL×3). Thecombined organic layers are dried over anhydrous sodium sulfate,concentrated and purified by silica gel column chromatography (PE 100%)to give 218 as an oil (170 mg, 62%). (MS: [M+H]⁺ 285.0)

Step 2: Phenol 219

To a solution of 218 (660 mg, 2.32 mmol) in DCM (20 mL) is added borontribromide (580 mg, 2.32 mmol) at 0° C. slowly. After stirring at roomtemperature for 3 hours, IN HCl is added and the mixture is extractedwith DCM (10 mL×3). The combined organic layers are dried, concentrated,and purified by silica gel column chromatography (EA:PE=1:20) to give219 as an oil. (480 mg, 77%). (MS: [M+H]⁺ 269.0)

Step 3: Chloride 220

To a solution of 219 (480 mg, 1.77 mmol), Py (0.15 mL, 1.77 mmol) intoluene is added thionyl chloride (0.25 mL, 3.54 mmol). After stirringat room temperature for 1 hour, the mixture is concentrated andpartitioned between DCM and IN HCl aqueous solution. The organic layeris washed with water, dried, filtered, and concentrated to give 220 asan oil (500 mg, 98%). (MS: [M+H]⁺ 287.0)

Step 4: Phenol 221

To a solution of 220 (500 mg, 1.736 mmol) in THF (20 mL) is added sodiumborohydride (131 mg, 3.47 mmol). After stirring at room temperature for3 hours, IN HCl is added and the mixture is extracted with EA, dried,and concentrated to give 221 as an oil (360 mg, 82%). (MS: [M+H]⁺ 255.1)

Step 5: CB8

Prepared by essentially the same method as for C11. (MS: [M+H]⁺ 283.0)

Preparation of CB9

To a solution of 141 (231 mg, 1.0 mmol) and 222 (200 mg, 1.2 mmol) inDMF (15 mL) is added potassium tert-butoxide (135 mg, 1.2 mmol). Afterstirring at 100° C. for 8 hours, the mixture is concentrated andpurified by silica gel column chromatography (EA:PE=1:3) to give CB9 asa yellow solid (175 mg, 54%). (MS: [M+H]⁺ 383.2)

Preparation of CB10

Step 1: Iodide 224

To a solution of 223 (300 mg, 1.34 mmol) in DMF (5 mL) is addedpotassium hydroxide (98 mg 1.74 mmol) followed by iodine (408 mg 1.61mmol). After stirring at room temperature for 2 hours, the mixture isdiluted with EA (100 mL), washed with brine (30 mL×3), dried overanhydrous sodium sulfate, filtered, concentrated and purified by silicagel column chromatography (EA:PE=1:3) to give 224 as a white solid (310mg, 66%). (MS: [M+H]⁺349.9)

Step 2: Iodide 225

To a solution of 224 (300 mg, 0.85 mmol) in THF (10 mL) is added NaH (51mg, 1.29 mmol) and stirred for 10 minutes before triisopropylsilylchloride (198 mg, 1.03 mmol) is added at 0° C. After stirring at roomtemperature for 2 hours, saturated ammonium chloride aqueous solutionand EA (100 mL) are added. The organic layer is washed with brine (30mL×3), dried over anhydrous sodium sulfate, filtered, concentrated, andpurified by silica gel column chromatography (EA:PE=1:5) to give 225 asa white solid (400 mg, 92%). (MS: [M+H]⁺ 506.0)

Step 3: CB10

To a mixture of 225 (200 mg, 0.39 mmol), 226 (118 mg, 0.39 mmol), andsodium carbonate (83.7 mg, 0.79 mmol) in dioxane (5 mL) and water (0.5mL) is added Pd(dppf)Cl₂ (50 mg, 0.07 mmol). After stirring at 90° C.for 2 hours, the mixture is diluted with EA (50 mL), filtered,concentrated, and purified by silica gel column chromatography(EA:PE=1:3) to give CB10 as a white solid (87 mg, 40%). (MS: [M+H]⁺553.2)

Preparation of CB11

Prepared by essentially the same method as for C18. (MS: [M+H]⁺ 362.0)

Preparation of CB12

Prepared by essentially the same method as for CB10. (MS: [M+H]⁺ 533.1)

Preparation of D

Preparation of D1

To a mixture of 233 (20 g, 171 mmol) and potassium carbonate (47.3 g,342 mmol) in DMF (100 mL) is added MeI (32 mL, 513 mmol) dropwise at 0°C. After stirring at room temperature for 12 hours, the mixture isconcentrated and the residue is partitioned between water (100 mL) andDCM (100 mL). The aqueous layer is extracted with DCM (60 mL×4). Thecombined organic layers are dried over anhydrous sodium sulfate,filtered, concentrated, and purified by silica gel column chromatography(DCM) to give D1 as an off-white solid (10 g, 50% yield). (MS: [M+H]⁺132.2)

The following compound is prepared by essentially the same method as forD1.

Intermediate Structure MS D2

[M + H]⁺ 146.0Preparation D3

To a solution of 234 (500 mg, 4.9 mmol) and TEA (1.1 mL, 7.4 mmol) inEtOH (10 mL) is added ethyl 2-bromoacetate (814 mg, 4.9 mmol). Afterstirring at 60° C. for 2 hours, the mixture is cooled to roomtemperature, diluted with water (5 mL) and EA (100 mL). The layers areseparated and the organic layer is washed with water (10 mL×3), driedover anhydrous sodium sulfate, and concentrated to give D3 as a whitesolid (77 mg, 7% yield)

The following compound is prepared by essentially the same method as forD3.

Intermediate Structure MS D4

—Preparation of D5

Step 1: Ester 237

To a solution of 236 (30 g, 218 mmol) in EtOH (300 mL) is added sodiumcarbonate (25 g, 237 mmol) and ethyl 2-mercaptoacetate (31 mL, 283mmol). After stirring at 90° C. for 2.5 hours, the mixture is cooled toroom temperature and water (500 mL) is added. The solid is collected byfiltration, washed with water, and dried to give 237 as a yellow solid(45 g, 94% yield). (MS: [M+H]⁺ 223.3)

Step 2: Acid 238

To a solution of 237 (20.0 g, 90.1 mmol) in EtOH (500 mL) and water (500mL) is added NaOH (7.2 g, 180 mmol) in portions. After stirring at 70°C. for 45 minutes, the mixture is cooled to 0° C. and is acidified withconcentrated HCl to pH 5. The yellow solid is then collected byfiltration and dried to give 238 (17 g, 98% yield). (MS: [M+H]⁺ 195.2)

Step 3: D5

A solution of 238 (17 g, 87 mmol) in phosphoric acid (150 mL, 85%aqueous solution) is stirred at 100° C. for 45 minutes. Saturatedaqueous sodium bicarbonate solution is then added at room temperature toadjust to pH 8. The solid is collected by filtration and washed withEtOH (100 mL×2) to give D5 as an orange solid (9.0 g, 54% yield). (MS:[M+H]⁺ 152.1)

The following compounds are prepared by essentially the same method asfor D5 except DMF was used as the solvent for the first step.

Intermediate Structure MS D6

[M + H]⁺ 169.9 D7

[M + H]⁺ 152.1 D8

[M + H]⁺ 153.0 D9

—Preparation D10

A solution of 239 (0.76 g 10 mmol), ethyl 2-chloroacetate (2.1 mL, 20mmol), and sodium acetate in EtOH (100 mL) is stirred at 60° C.overnight. After cooling to room temperature, the solid is collected togive D10 as a white solid (0.65 g, 55% yield). (MS: [M+H]⁺ 117.2)

Preparation of DA1

Step 1: Acid 241

A mixture of 240 (1.0 g, 10 mmol) and NaOH (0.8 g, 2.0 mmol) in EtOH (20mL) is stirred at 80° C. for 1 hour before chloroacetic acid (1.03 g,1.1 mmol) is added. After stirring at 80° C. for 2 hours, the mixture isconcentrated and concentrated HCl (4 mL) is added. The mixture is thenstirred at room temperature for 10 minutes before concentrated to give241 as a yellow solid (2.5 g, 100%). (MS: [M+H]⁺ 159.1)

Step 2: DA1

To a solution of 241 (1.0 g 6.3 mmol) in Py (10 mL) is added aceticanhydride (3 mL). After stirring at 55° C. for 40 minutes, the mixtureis diluted with EA (100 mL), washed with water (40 mL×3), dried overanhydrous sodium sulfate, filtered, concentrated, and purified by silicagel column chromatography (EA:PE=1:2) to give DA1 as a yellow solid (150mg, 17%). (MS: [M+H]⁺ 141.1)

Preparation of DB1

To a mixture of 242 (500 mg, 4.81 mmol) and sodium acetate (1.97 g, 24.1mmol) in EtOH (20 mL) is added ethyl 2-chloroacetate (1.17 g, 9.62mmol). After stirring at 60° C. overnight, the mixture is concentratedand purified by silica gel column chromatography (EA:PE=1:10) to giveDB1 as a white solid (619 mg, 90%). (MS: [M+H]⁺145.0)

Preparation of DB2

Step 1: Nitrosothiourea 242

To a mixture of 242 (1.04 g, 10 mmol) and sodium nitrite (696 mg, 10.1mmol) in DCM (10 mL) is added 0.1 N HCl (20 mL, 200 mmol). Afterstirring at −10° C. to 5° C. for 4 hours, the mixture is extracted withDCM (100 mL×3). The combined organic layers are dried over anhydroussodium sulfate, filtered, and purified by silica gel columnchromatography (EA:PE=1:30) to give 243 as a yellow oil (224 mg, 17%).(MS: [M+H]⁺134.0)

Step 2: Thiourea 244

To a mixture of 243 (224 mg, 1.66 mmol) in MeCN (3 mL) is addedethylamine (225 mg, 5 mmol). After stirring at room temperatureovernight, the mixture is concentrated and purified by silica gel columnchromatography (EA:PE=1:10) to give 244 as a solid (90 mg, 46%). (MS:[M+H]⁺ 119.0)

Step 3: DB2

Prepared by essentially the same method as for DB1. (MS: [M+H]⁺ 159.2)

Preparation of DB3

Prepared by essentially the same method as for DB2. (MS: [M+H]⁺ 173.2)

Preparation of E

Preparation of E1

To a solution of C1 (100 mg, 0.43 mmol) in EtOH (5 mL) is D1 (57 mg,0.43 mmol) and piperidine (37 mg, 0.43 mmol). After stirring at 80° C.for 4 hours, the solid is collected by filtration and washed with EtOH.Recrystallization from EtOH gives E1 (32 mg, 21% yield) as a yellowsolid. (MS: [M+H]⁺ 344.2)

The following compounds are prepared by essentially the same method asfor E1.

Intermediate Building blocks Structure MS E2

[M + H]⁺ 374.0 E3

[M + H]⁺ 392.0 E4

[M + H]⁺ 343.0 E5

[M + H]⁺ 394.0 E6

[M + H]⁺ 412.0 E7

[M + H]⁺ 361.9 E8

[M + H]⁺ 364.0 E9

[M + H]⁺ 354 E10

[M + H]⁺ 338 E11

[M + H]⁺ 343.9Preparation of E12

Step 1: Ether 246

To a solution of E1 (200 mg, 0.58 mmol) in MeCN (5 mL) is added 182 (104mg, 0.58 mmol) and cesium carbonate (474 mg, 1.46 mmol). After stirringat 70° C. for 3 hours, the mixture is concentrated and purified bysilica gel column chromatography (MeOH:DCM=0:100 to 1:200) to give 246as a yellow solid (100 mg, 39% yield). (MS: [M+H]⁺ 442.1)

Step 2: E12

To a solution of 246 (200 mg, 0.45 mmol) and TEA (0.3 mL, 2.26 mmol) inDCM (10 mL) is added acetyl chloride (0.06 mL, 0.9 mmol) dropwise atroom temperature. After stirring for 3 hours, water is added and thesolid is collected by filtration, washed with water, and dried to givecrude E12 as a yellow solid (170 mg, 78% yield). (MS: [M+H]⁺484.2)

Preparation of E13

To a solution of 246 (100 mg, 0.23 mmol) in DCM (10 mL) is added borontribromide (180 mg, 0.7 mmol) dropwise at 0° C. After stirring at roomtemperature for 3 hours, water (2 mL) is added at 0° C. The organiclayer is dried over anhydrous sodium sulfate, filtered, and concentratedto crude E13 as a yellow solid (80 mg, 52% yield). (MS: [M+H]⁺ 428.1)

Preparation of E14

A mixture of E2 (200 mg, 0.53 mmol), DMF (3 mL), potassium carbonate(148 mg, 1.07 mmol), and propargyl bromide (0.1 mL, 1.04 mmol) isstirred at room temperature for 3 hours. The mixture is then dilutedwith water (10 mL) and extracted with EA (10 mL×3). The combined organiclayers are dried over anhydrous sodium sulfate, filtered, andconcentrated to crude E14 as a yellow solid (228 mg, 100% yield). (MS:[M+H]⁺412.1)

The following compounds are prepared by essentially the same method asfor E14.

Inter- mediate Building blocks Structure MS E15

[M + H]⁺ 545.9 E16

[M − MOM + 2H]⁺ 498 E17

[M − MOM + 2H]⁺ 496 E18

[M − MOM + 2H]⁺ 470 E19

[M − MOM + 2H]⁺ 454Preparation of E20

A E2 (55 mg 0.1 mmol), 247 (22 mg 0.1 mmol), and triphenylphosphine (58mg 0.2 mmol) in THF (3 mL) is stirred at room temperature for 10minutes. DIAD (44 mg 0.2 mmol) is then added at −5° C. After stirring atroom temperature for 16 hours, the mixture is concentrated and purifiedby silica gel column chromatography (MeOH:DCM=1:100) to give E20 as ayellow solid (35 mg, 45% yield). (MS: [M+H]⁺ 480.0)

The following compounds are prepared by essentially the same method asfor E20.

Inter- mediate Building blocks Structure MS E21

[M + H]⁺ 512.0 E22

[M + H]⁺ 532.0Preparation of E23

Step 1: Ether 248

To a solution of B20 (100 mg, 0.27 mmol) and E2 (100 mg, 0.27 mmol) inDMF (5 mL) is added potassium carbonate (74.4 mg, 0.54 mmol) at roomtemperature. After stirring at room temperature for 1 hour, the mixtureis filtered, concentrated, and purified by silica gel columnchromatography (EA:PE=1:1) to give 248 as a yellow solid (150 mg, 86%yield). (MS: [M+H]⁺ 651.1)

Step 2: E23

To a solution of 248 (150 mg 0.23 mmol) in DCM (4 mL) is added TFA (2mL) dropwise at 0° C. After stirring at room temperature for 2 hours,the mixture is concentrated and triturated with MeOH (5 mL). The solidis collected by filtration and dried to give E23 as a light yellow solid(78 mg 67% yield). (MS: [M+H]⁺ 507.0)

Preparation of E24

To a mixture of E11 (400 mg, 1.16 mmol) and phenylboronic acid (425 mg,3.49 mmol) in DCM (10 mL) is added Cu(OAc)₂ (253 mg, 1.39 mmol) and TEA(588 mg, 5.81 mmol). After stirring at room temperature overnight, themixture is filtered, concentrated, and triturated with EtOH (5 mL). Thesolid is collected by filtration to give E24 as a yellow solid (208 mg,43% yield). (MS: [M+H]⁺ 420.1)

The following compounds are prepared by essentially the same method asdescribed above.

Refer- ence Inter- of prep- mediate Building blocks Structure MS arationEA1

[M − H]⁻ 398.0 E1 EA2

[M + H]⁺ 695.1 E20 EA3

[M + H]⁺ 550.0 E14 EA4

[M + H]⁺ 596.0 E14 EA5

— E14

EXAMPLES

The following examples of compounds of the invention were made andtested according to the procedures and methods described herein.

Chemistry Example 1

A solution of 249 (11 mg, 0.1 mmol), 233 (12 mg, 0.1 mmol), andβ-alanine (11 mg, 0.12 mmol) in acetic acid (0.5 mL) is stirred underrefluxed for 3 hours. The solid is collected and washed with acetic acid(0.5 mL) to give Ex1 as a white solid (20 mg, 97% yield). (MS: [M+H]⁺207.2)

The following compounds are prepared by essentially the same method asfor Ex1.

Example Building blocks Structure MS Ex2

[M + H]⁺ 207.2 Ex3

[M + H]⁺ 221.2 Ex4

[M + H]⁺ 275.2 Ex5

[M + H]⁺ 247.2 Ex6

[M + Na]⁺ 218.0 Ex7

[M + H]⁺ 208.2 Ex8

[M − H]⁻ 206.2 Ex9

[M + H]⁺ 206.2

Example 10

To a solution of 250 (79 mg, 0.27 mmol) in DCM (0.6 mL) is added borontribromide (1 M in DCM, 0.4 mL, 0.4 mmol) at 0° C. After stirring atroom temperature for 3 hours, the mixture is concentrated and purifiedby silica gel flash chromatography (EA:hexanes=1:1) to give Ex10 as abrown solid (40 mg, 56% yield). (MS: [M−H]⁻ 268.2)

The following compound is prepared by essentially the same method as forEx10.

Example Building blocks Structure MS Ex11

[M + H]⁺ 330.2

The following compound is prepared by essentially the same method as forEx1.

Example Building blocks Structure MS Ex12

[M + H]⁺ 221.0 Ex13

[M + H]⁺ 292.2

Example 14

A mixture of 249 (200 mg, 1.87 mmol), 251 (187 mg, 1.87 mmol), glycine(140 mg, 1.87 mmol), and sodium carbonate (98 mg, 0.94 mmol) in water (2mL) is stirred at reflux for 3 hours. After cooling to room temperature,the solid is collected and washed with water (0.5 mL) to give Ex14 as apink solid (28 mg, 8% yield). (MS: [M+H]⁺ 190.2)

The following compound is prepared by essentially the same method as forEx14.

Example Building blocks Structure MS Ex15

[M + H]⁺ 191.2

Example 16

A mixture of C1 (200 mg, 0.87 mmol), 240 (87 mg, 0.87 mmol), ethyl2-chloroacetate (0.082 mL, 0.87 mmol), and sodium acetate in HOAc (5 mL)is stirred at reflux overnight. After cooling to room temperature, thesolid is collected, washed with water (0.5 mL), and purified by prep-TLC(EA:hexanes=1:1) to give Ex16 as a yellow solid (0.8 mg, 0.3% yield).(MS: [M+H]⁺ 354.9)

The following compound is prepared by essentially the same method as forEx16.

Example Building blocks Structure MS Ex17

[M + H]⁺ 367.0

Example 18

A solution of E1 (17 mg, 0.05 mmol) and phosphorus pentasulfide (33 mg,0.075 mmol) in Py (1.0 mL) is stirred at 120° C. for 3 hours. Aftercooling to room temperature, one-fifth of the mixture is purified byHPLC (MeCN:water with 0.1% TFA=1:1 to 1:0) to give Ex18 as a yellowsolid (1.5 mg, 42% yield). (MS: [M+H]⁺ 360.2)

Example 19

Step 1: Alkyne 252

To a solution of C1 (115 mg, 0.5 mmol), CuI (10 mg, 0.05 mmol),trimethylsilylacetylene (0.083 mL, 0.55 mmol), and DIPA (0.5 mL) in DMF(1.0 mL) and THF (5.0 mL) is added Pd(PPh₃)₄ (30 mg, 0.026 mmol) at roomtemperature. After stirring at 88° C. for 1 hour, the mixture is cooledto room temperature, filtered, diluted with EA (10 mL), washed withwater (5 mL) and brine (5 mL), dried over anhydrous sodium sulfate, andpurified by prep-TLC (EA:hexanes=1:2) to give 252 as a white solid (50mg, 40% yield). (MS: [M+H]⁺ 249.0)

Step 2: Thiazolidinedione 253

A solution of 252 (10 mg, 0.04 mmol), D1 (7 mg, 0.05 mmol), andpiperidine (0.002 mL, 0.02 mmol) in EtOH (0.4 mL) is stirred underreflux for 2 hours and then cooled to room temperature. The mixture ispurified on prep-TLC (EA:hexanes=1:1) to give 253 as a white solid (10mg, 69% yield). (MS: [M+H]⁺ 362.2)

Step 3: Ex19

To a solution of 253 (3.5 mg, 0.01 mmol) in THF (0.5 mL) is addedtriethylamine trihydrofluoride (0.005 mL, 0.03 mmol). After stirring for2 hours, the mixture is purified by HPLC (MeCN:water with 0.1% TFA=2:3to 1:0) to give Ex19 as a white solid (2.0 mg, 71% yield). (MS: [M+H]⁺290.2)

Example 20

Step 1: Thiazolidinedione 254

A solution of crude 196 (394 mg), D1 (161 mg, 1.23 mmol), and piperidine(0.03 mL, 0.25 mmol) in EtOH (2 mL) is stirred at reflux for 2 hours andthen cooled to room temperature. The solid is collected to give 254 as awhite solid (256 mg, 68% yield for two steps). (MS: [M+H]⁺ 434.2)

Step 2: Bromide 255

To a solution of 254 (256 mg, 0.46 mmol) in DCM (4 mL) is added bromine(0.03 mL, 0.58 mmol) at 0° C. After stirring at room temperature for 1.5hours, saturated sodium thiosulfate (0.5 mL) is added and the mixture isextracted with EA (10 mL×3). The combined organic layers are washed withwater (5 mL) and brine (5 mL), dried over anhydrous sodium sulfate,concentrated and purified by silica gel column chromatography(EA:hexanes=1:1) to give 255 as a white solid (37 mg, 14% yield).

Step 3: Bromide 256

To a solution of 255 (37 mg, 0.062 mmol) in DCM (2 mL) is added DBU(0.02 mL, 0.124 mmol) at 0° C. After stirring at room temperature for 4hours, 1 N HCl (0.5 mL) is added and the mixture is extracted with EA (5mL×3). The combined organic layers are washed with water (3 mL) andbrine (3 mL), dried over anhydrous sodium sulfate, concentrated, andpurified by prep-TLC (EA:hexanes=1:1) to give 256 as a colorless oil (5mg, 16% yield). (MS: [M+H]⁺ 512.0)

Step 4: Ex20

To a solution of 256 (77 mg, 0.15 mmol) and dimethylsulfide (0.03 mL,0.45 mmol) in DCM (3 mL) is added boron trifluoride diethyl etherate(0.06 mL, 0.45 mmol) at 0° C. After stirring at room temperature for 5hours, saturated sodium bicarbonate (1 mL) is added and the mixture isextracted with EA (10 mL×3). The combined organic layers are washed withwater (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate,concentrated, and purified by prep-TLC (EA:hexanes=1:2) to give Ex20 asa yellow oil (24 mg, 38% yield). (MS: [M+H]⁺ 422.0)

Example 21

To a solution of E4 (100 mg 0.29 mmol) and TEA (88 mg 0.87 mmol) in DCM(2.5 mL) and DCE (2.5 mL) is added 257 (100 mg 0.58 mmol) at 0° C. Afterstirring at 60° C. overnight, the mixture is filtered, concentrated, andpurified by silica gel column chromatography (MeOH:DCM=1:30) to giveEx21 as a yellow solid (7 mg, 5% yield). (MS: [M+H]⁺ 486)

The following compounds are prepared by essentially the same method asfor Ex21.

Ex- ample Building blocks Structure MS Ex22

[M + Na]⁺ 443.0 Ex23

[M + Na]⁺ 504.8 Ex24

[M + H]⁺ 497.2

Example 25

Step: Phenol 258N

To a solution of E4 (250 mg, 0.73 mmol) in DCM (10 mL) is added borontribromide (547 mg, 2.19 mmol) at −78° C. slowly. After stirring at −78°C. for 1 hour and then at room temperature for 1.5 hours, water (2 mL)is added at −30° C. The solid is collected by filtration and dried toprovide 258 as a yellow solid (230 mg, 96% yield). (MS: [M+H]⁺ 329.1)

Step 2: Ex25

A mixture of 258 (50 mg, 0.15 mmol) and CDI (49 mg, 0.30 mmol) in THF (2mL) is stirred at room temperature overnight. The mixture is thenfiltered and triturated with MeOH (5 mL) to give Ex25 as a yellow solid(20 mg, 37% yield). (MS: [M+H]⁺ 355.1)

The following compound is prepared by essentially the same method as forEx25.

Example Building blocks Structure MS Ex26

[M + H]⁺ 374.9

Example 27

To a solution of E24 (50 mg, 0.12 mmol) in DCM (5 mL) is added borontribromide (89.4 mg, 0.36 mmol) at −78° C. slowy. After stirring at −78°C. for 1 hour and then at room temperature overnight, water (2 mL) isadded at −30° C. and the mixture is concentrated and purified byprep-HPLC to give Ex27 as a white solid (15 mg, 31% yield). (MS: [M+H]⁺406.1)

Example 28

Prepared as described above for E1.

The following compounds are prepared by essentially the same method asfor Ex28.

Example Building blocks Structure MS Ex29

[M + H]⁺ 284.0 Ex30

[M + H]⁺ 300.2 Ex31

[M + H]⁺ 334.1 Ex32

[M + Na]⁺ 380.0 Ex33

[M + Na]⁺ 390.0 Ex34

[M + Na]⁺ 399.8 Ex35

[M + H]⁺ 396.2 Ex36

[M + H]⁺ 339.2 Ex37

[M + Na]⁺ 392.0 Ex38

[M + Na]⁺ 381.8 Ex39

[M + H]⁺ 358.1 Ex40

[M + H]⁺ 355.0 Ex41

[M + H]⁺ 311.0 Ex42

[M + H]⁺ 369.0 Ex43

[M + H]⁺ 325.0 Ex44

[M + H]⁺ 362.9 Ex45

[M + H]⁺ 364.0 Ex46

[M + H]⁺ 398.2 Ex47

[M + H]⁺ 441.8 Ex48

[M + H]⁺ 382.0 Ex49

[M + H]⁺ 364.0 Ex50

[M + H]⁺ 365.0 Ex51

[M + H]⁺ 365.2 Ex52

[M + H]⁺ 313.9 Ex53

[M + H]⁺ 420.9 Ex54

[M + H]⁺ 541.0 Ex55

[M + H]⁺ 541.0 Ex56

[M + H]⁺ 541.0 Ex57

[M + H]⁺ 397.9 Ex58

[M + H]⁺ 342.1 Ex59

[M − H]⁻ 354   Ex60

[M + H]⁺ 474.9 Ex61

[M + H]⁺ 504.9 Ex62

[M + H]⁺ 623.1 Ex63

[M + H]⁺ 361.9 Ex64

[M + H]⁺ 280.1 Ex65

[M + H]⁺ 391.9 Ex66

[M + H]⁺ 337.1 Ex67

— Ex68

[M + H]⁺ 463.0 Ex69

— Ex70

[M + H]⁺ 417.9 Ex71

[M + Na]⁺ 358.1 Ex72

[M + H]⁺ 441.0 Ex73

[M + H]⁺ 457.0 Ex74

[M + H]⁺ 462.0 Ex75

[M + H]⁺ 381.9 Ex76

[M + H]⁺ 300.1 Ex77

[M + H]⁺ 411.9 Ex78

[M + H]⁺ 359.1 Ex79

[M + H]⁺ 362.0

Example 80

Step 1: Phenol 222

To a solution of C27 (60 mg, 0.16 mmol) in DCM is added TFA (1 mL)dropwise at 0° C. After stirring at room temperature for 2 hours, themixture is concentrated to give crude 259 as a yellow oil (40 mg, 75%yield). (MS: [M+H]⁺ 339.3)

Step 2: Ex80

To a solution of 259 (40 mg, 0.12 mmol) in EtOH (1 mL) is addedpiperidine (10 mg, 0.12 mmol) and D1 (16 mg, 0.12 mmol). After stirringat 60° C. for 12 hours, the mixture is concentrated and purified byprep-HPLC to give Ex80 as a yellow solid (3.6 mg, 7% yield). (MS: [M+H]⁺453)

The following compounds are prepared by essentially the same method asfor Ex80.

Example Building blocks Structure MS Ex81

[M + H]⁺ 455.1 Ex82

[M + H]⁺ 452.8 Ex83

[M + H]⁺ 514  

The following compounds are prepared by essentially the same method asfor E23.

Example Building blocks Structure MS Ex84 

[M + H]⁺ 451.0 Ex85 

[M + H]⁺ 386.0 Ex86 

[M + H]⁺ 426.0 Ex87 

[M + H]⁺ 497.0 Ex88 

[M + H]⁺ 420.0 Ex89 

[M + H]⁺ 421.0 Ex90 

[M + H]⁺ 421.0 Ex91 

[M + H]⁺ 527.0 Ex92 

[M + H]⁺ 410.0 Ex93 

[M + H]⁺ 455.9 Ex94 

[M + H]⁺ 462.1 Ex95 

[M + H]⁺ 507.0 Ex96 

[M + H]⁺ 499.0 Ex97 

[M + H]⁺ 499.0 Ex98 

[M + H]⁺ 501.9 Ex99 

[M + H]⁺ 498.0 Ex100

[M + H]⁺ 513.9 Ex101

[M + H]⁺ 422.0 Ex102

[M + H]⁺ 451.9 Ex103

[M + H]⁺ 436.0 Ex104

[M + H]⁺ 469.9 Ex105

[M + H]⁺ 465.0 Ex106

[M + H]⁺ 439.0 Ex107

[M + H]⁺ 473.9 Ex108

[M + H]⁺ 469.0 Ex109

[M + H]⁺ 495.0 Ex110

[M + H]⁺ 469.0 Ex111

[M + H]⁺ 483.0 Ex112

[M + H]⁺ 387.0 Ex113

[M + H]⁺ 441.0 Ex114

[M + H]⁺ 456.0 Ex115

[M + H]⁺ 475.9 Ex116

[M + H]⁺ 471.0 Ex117

[M + H]⁺ 497.0 Ex118

[M + H]⁺ 525.0 Ex119

[M + H]⁺ 455.0 Ex120

[M + H]⁺ 470.0 Ex121

[M + H]⁺ 490.0 Ex122

[M + H]⁺ 471.0 Ex123

[M + H]⁺ 475.0 Ex124

[M + H]⁺ 489.0

Example 125

Step 1: pyridinone 260

To a solution of E2 (50 mg 0.14 mmol),5-(hydroxymethyl)pyridin-2(1H)-one (20 mg, 0.16 mmol), and PPh₃ (42 mg,0.16 mmol) in THF (2 mL) is added DIAD (54 mg 0.27 mmol) at roomtemperature. After stirring at 30° C. overnight, the mixture isconcentrated, triturated with EtOH (3 mL), and collected by filtrationto give 260 as a white solid (23 mg 36% yield). (MS: [M+H]⁺ 481.1)

Step 2: Ex125

A mixture of 260 (20 mg, 0.05 mmol) and 2M HCl in MeOH (5 mL) is stirredat room temperature for 3 hours. The mixture is then concentrated andpurified by prep-TLC (MeOH:DCM=1:20) to give Ex125 as a yellow solid (4mg, 22% yield). (MS: [M+H]⁺437.2)

The following compounds are prepared by essentially the same method asfor Ex125.

Example Building blocks Structure MS Ex126

[M + H]⁺ 441.0 Ex127

[M + H]⁺ 531.1 Ex128

[M + H]⁺ 532.0 Ex129

[M + H]⁺ 532.0 Ex130

[M + H]⁺ 532.0 Ex131

[M + H]⁺ 436.0 Ex132

[M + H]⁺ 436.0 Ex133

[M + H]⁺ 436.0 Ex134

[M + H]⁺ 437.0 Ex135

[M + H]⁺ 479.0 Ex136

[M + H]⁺ 513.0 Ex137

[M + H]⁺ 410.0 Ex138

[M + H]⁺ 437.0 Ex139

[M + H]⁺ 437.0 Ex140

[M + H]⁺ 422.0 Ex141

[M + H]⁺ 437.0 Ex142

[M + H]⁺ 436.0 Ex143

[M + H]⁺ 452.0 Ex144

[M + H]⁺ 468.0 Ex145

[M + H]⁺ 498.0 Ex146

[M + H]⁺ 499.0 Ex147

[M + H]⁺ 437.0 Ex148

[M + H]⁺ 451.0 Ex149

[M + H]⁺ 477.0 Ex150

[M + H]⁺ 479.0 Ex151

[M + H]⁺ 493.0 Ex152

[M + H]⁺ 499.0 Ex153

[M + H]⁺ 515   Ex154

[M + H]⁺ 527.0 Ex155

[M + H]⁺ 528.0 Ex156

[M + H]⁺ 528.0 Ex157

[M + H]⁺ 528.0 Ex158

[M + H]⁺ 513.0 Ex159

[M + H]⁺ 514.0 Ex160

[M + H]⁺ 514.0 Ex161

[M + H]⁺ 542.0 Ex162

[M + H]⁺ 465.0 Ex163

[M + H]⁺ 490.0 Ex164

[M + H]⁺ 505.0 Ex165

[M + H]⁺ 506.0 Ex166

[M + H]⁺ 507.0 Ex167

[M + H]⁺ 520.3 Ex168

[M + H]⁺ 488.0 Ex169

[M + H]⁺ 488.0 Ex170

[M + H]⁺ 451.0 Ex171

[M + H]⁺ 477.0 Ex172

[M + H]⁺ 505.0 Ex173

[M + H]⁺ 471.0 Ex174

[M + H]⁺ 471.0 Ex175

[M + H]⁺ 471.0 Ex176

[M + H]⁺ 471.0 Ex177

[M + H]⁺ 471.0 Ex178

[M + H]⁺ 471.0 Ex179

[M + H]⁺ 435.0 Ex180

[M + H]⁺ 450.0 Ex181

[M + H]⁺ 495.0 Ex182

[M + H]⁺ 509.0 Ex183

[M + H]⁺ 465.0 Ex184

[M + H]⁺ 452.0 Ex185

[M + H]⁺ 440.0 Ex186

[M + H]⁺ 436   Ex187

[M + H]⁺ 469.0 Ex188

[M + H]⁺ 546.0 Ex189

[M + H]⁺ 546.0 Ex190

[M + H]⁺ 546.0 Ex191

[M + H]⁺ 560.0 Ex192

[M + H]⁺ 454.0 Ex193

[M + H]⁺ 442.0 Ex194

[M + H]⁺ 457.0 Ex195

[M + H]⁺ 471.0 Ex196

[M + H]⁺ 501.0 Ex197

[M + H]⁺ 515.0 Ex198

[M + H]⁺ 548.0 Ex199

[M + H]⁺ 548.0 Ex200

[M + H]⁺ 548.0

Example 201

To a solution of E1 (200 mg, 0.58 mmol) in DMF (10 mL) is added2-bromo-1,3,4-thiadiazole (192 mg, 1.16 mmol) and cesium carbonate (568mg, 1.74 mmol). After stirring at 70° C. for 4 hours, the mixture isconcentrated and purified by prep-TLC (EA:PE=1:1) to give Ex201 as ayellow solid (4 mg, 2% yield). (MS: [M+H]⁺ 428.1)

The following compounds are prepared by essentially the same method asfor Ex201.

Example Building blocks Structure MS Ex202

[M + H]⁺ 421.0

The following compounds are prepared by essentially the same method asfor Ex125.

Example Building blocks Structure MS Ex203

[M + H]⁺ 435.0

Example 204

Following the procedure for 16 using E1 (200 mg, 0.58 mmol), DCM (10mL), quinoline-4-boronic acid (301 mg, 1.74 mmol), Cu(OAc)₂ (116 mg,0.64 mmol), and TEA (0.4 mL, 0.9 mmol), purify with prep-TLC(MeOH:DCM=1:20) to give Ex204 as a yellow solid (15 mg, 5% yield). (MS:[M+H]⁺ 471.1)

Example 205

A mixture of E1 (86 mg 0.25 mmol) and CuCN (27 mg 0.30 mmol) in DMF (1mL) is stirred at 150° C. for 4 hours. After cooling to roomtemperature, the mixture is partitioned between EA/dichloromethane (75mL, 1:1) and brine (25 mL). The layers are separated and the organiclayer is dried over anhydrous sodium sulfate, concentrated, and purifiedby silica gel column chromatography (EA:hexanes) to give Ex205 as ayellow solid (15 mg, 21% yield).

Example 206

Step 1: amide 261

To a solution of E12 (100 mg, 0.21 mmol) in DMF (2 mL) is added4-(bromomethyl)pyridine hydrobromide (104 mg, 0.42 mmol) and potassiumcarbonate (171 mg, 1.24 mmol). After stirring at 60° C. for 4 hours, themixture is concentrated and purified by prep-TLC (MeOH:DCM=1:20) to give261 as a yellow solid (30 mg, 25% yield). (MS: [M+H]⁺ 575.1)

Step 2: Ex206

A solution of 261 (30 mg, 0.05 mmol) in methanolic HCl (2M, 5 mL) isstirred at room temperature for 5 hours. The mixture is thenconcentrated and purified by prep-TLC (MeOH:DCM=1:20) to give Ex206 as ayellow solid (10 mg, 36% yield). (MS: [M+H]⁺533.1)

The following compound is prepared by essentially the same method as forEx206.

Exam- ple Building blocks Structure MS Ex207

[M + H]⁺ 533.0

Example 208

Step 1: Aldehyde 262

To a solution of E10 (380 mg, 1.1 mmol) in TFA (3 mL) is added HMTA (315mg, 2.2 mmol) at room temperature. After stirring at 100° C. for 20minutes under microwave irradiation, the mixture is cooled andconcentrated. The residue is partitioned between EA (30 mL) andsaturated sodium bicarbonate solution (20 mL). The aqueous layer isextracted with EA (20 mL×2). The combined organic layers are dried overanhydrous sodium sulfate, filtered, concentrated, and purified by silicagel column chromatography (EA:PE=1:5) to give 262 as a yellow solid (210mg, 51% yield). (MS: [M+H]⁺ 365.0)

Step 2: Hydrazone 263

To a mixture of 262 (50 mg, 0.1 mmol) in dioxane (2 mL) is addedtosylhydrazide (40 mg, 0.2 mmol) at room temperature. After stirring at80° C. for 2 hours, the mixture is concentrated and purified by prep-TLC(MeOH:DCM=1:10) to give 263 as a yellow solid (40 mg, 55% yield). (MS:[M+H]⁺ 533.0)

Step 3: Pyrimidine 265

To a mixture of 263 (40 mg, 0.07 mmol) in dioxane (2 mL) is addedpotassium carbonate (26 mg, 0.2 mmol) and 264 (51 mg, 0.1 mmol). Afterstirring at 120° C. for 2 hours, the mixture is cooled and filtered. Thesolid is washed by EA (10 mL×3) and the filtrate is concentrated to givecrude 265 as a brown solid (95 mg). (MS: [M+H]⁺ 644.1)

Step 4: Ex208

To a mixture of crude 265 (95 mg) in DCM (2 mL) is added TFA (4 mL)dropwise at room temperature. After stirring for 2 hours, the mixture isconcentrated and purified by prep-HPLC to give Ex208 as a yellow solid(5.0 mg, 15% yield). (MS: [M+H]⁺ 444.0)

Example 209

To a solution of E23 (100 mg, 0.2 mmol) in MeOH (20 mL) is added aqueousformaldehyde (37%, 1 mL) at room temperature and stirred for 2 hoursbefore sodium cyanoborohydride (31 mg, 0.5 mmol) is added. Afterstirring for 2 hours, the mixture is concentrated and triturated withsaturated sodium bicarbonate solution (5 mL). The solid is collected byfiltration, washed with water (1 mL), and dried to give Ex209 as ayellow solid (33.6 mg, 33% yield). (MS: [M+H]⁺ 521.1)

Example 210

To a solution of E9 (40 mg, 0.1 mmol) in DCM (3 mL) is added DAST (360mg, 2.2 mmol) dropwise at 0° C. After stirring at room temperature for 1hour, the mixture is poured into ice water (10 mL) and extracted withDCM (20 mL×3). The combined organic layers are dried over anhydroussodium sulfate, filtered, concentrated, and triturated with hexane andethanol (10:1, 22 mL). The solid is collected by filtration, washed withhexane, and dried to give Ex210 as a light yellow solid (30 mg, 71%yield). (MS: [M+H]⁺ 378.0)

Example 211

Following the procedure for Ex125 using E13 (80 mg, 0.18 mmol), THF (10mL) A13 (28 mg, 0.22 mmol), PPh₃ (98 mg, 0.37 mmol), and DIAD (57 mg,0.28 mmol), gives Ex211 as a yellow solid (10 mg, 8% yield). (MS: [M+H]⁺535.1)

Example 212

Step 1: Sulfoxide 266

A solution of E16 (27.1 mg, 0.05 mmol) and mCPBA (10.0 mg, 0.06 mmol),in DCM (5 mL) is stirred at 0 to 10° C. for 6 hours. Saturated sodiumbicarbonate solution is then added and the mixture is extracted with EA(5 mL×3). The combined organic layers are dried over anhydrous sodiumsulfate, filtered, concentrated, and purified by silica gel columnchromatography (MeOH:DCM=1:20 to 1:9) to give 266 as a yellow solid(13.8 mg, 50% yield). (MS: [M+H]⁺ 557.9)

Step 2: Ex212

To a solution of 266 (13.8 mg, 0.025 mmol) in DCM (5 mL) is added TFA (1mL) dropwise at 0° C. After stirring at room temperature for 1 hour, themixture is concentrated and triturated with MeOH (1 mL). The solid iscollected by filtration and dried to give Ex212 as a yellow solid (6.2mg, 49% yield). (MS: [M+H]⁺ 514.0)

The following compounds are prepared by essentially the same method asfor Ex212.

Example Building block Structure MS Ex213

[M + H]⁺ 484.0 Ex214

[M + H]⁺ 517.9 Ex215

[M + H]⁺ 512.0 Ex216

[M + H]⁺ 504.0

Example 217

To a solution of Ex213 (57 mg, 118 mmol) in THF (5 mL) is added NaOH(9.4 mg, 235 mmol) and water (0.2 ml). After stirring at 0 to 10° C. for6 hours, the mixture is concentrated to remove THF and 1M HCl is addedto reach pH 5. The mixture is then extracted with EA (5 mL×3). Thecombined organic layers are dried over anhydrous sodium sulfate,concentrated, triturated with MeOH (2 mL), collected by filtration,washed with MeOH (0.5 mL) to give Ex217 as a yellow solid (30 mg, 58%yield). (MS: [M+H]⁺ 438.0)

The following compound is prepared by essentially the same method as forEx217.

Example Building block Structure MS Ex218

[M + H]⁺ 438.0

Example 219

To a solution of Ex213 (50 mg, 103 mmol) in THF (2 mL) is added sodiumhydrosulfide (11 mg, 206 mmol) and water (0.5 ml). After stirring at 0to 10° C. for 6 hours, the mixture is concentrated to remove THF and 1MHCl is added to reach pH 5. The mixture is then extracted with EA (5mL×3). The combined organic layers are dried over anhydrous sodiumsulfate, concentrated, triturated with MeOH (2 mL), collected byfiltration, washed with MeOH (0.5 mL) to give Ex219 as a yellow solid(18 mg, 38% yield). (MS: [M+H]⁺ 454.0)

Example 220

Step 1: Sulfone 267

To a solution of E16 (27 mg, 0.05 mmol) in DCM (5 mL) is added mCPBA (10mg, 0.06 mmol). After stirring at 0 to 10° C. for 6 hours, saturatedsodium bicarbonate solution is added and the mixture is extracted withEA (5 mL×3). The combined organic layers are dried over anhydrous sodiumsulfate, filtered, concentrated, and purified by silica gel columnchromatography (MeOH:DCM=1:20 to 1:9) to give 267 as a yellow solid(13.6 mg, 47% yield). (MS: [M+H]⁺ 574.1)

Step 2: Ex220

To a solution of 267 (13.6 mg 0.024 mmol) in DCM (5 mL) is added TFA (1mL) dropwise at 0° C. After stirring at room temperature for 1 hour, themixture is concentrated and triturated with MeOH (1 mL). The solid iscollected by filtration and dried to give Ex220 as a yellow solid (6.0mg 47% yield). (MS: [M+H]⁺ 530.0)

The following compound is prepared by essentially the same method as forEx220.

Example Building block Structure MS Ex221

[M + H]⁺ 533.9

Example 222

Ammonia is bubbled through a solution of Ex220 (100 mg, 0.19 mmol) inTHF at −78° C. for 2 minutes in a sealing tube. After stirring at roomtemperature overnight, the mixture is concentrated and triturated withMeOH (1 mL). The solid is then collected by filtration and dried to giveEx222 as a yellow solid (13.2 mg, 15% yield). (MS: [M+H]⁺467.0)

The following compound is prepared by essentially the same method as forEx222.

Example Building block Structure MS Ex223

[M + H]⁺ 465.0

Example 268

Step 1: Amide 268

To a solution of E20 (20 mg, 0.04 mmol) in DCM (2 mL) is addednicotinoyl chloride (9 mg, 0.06 mmol) and TEA (9 mg, 0.08 mmol). Afterstirring at room temperature for 16 hours, the mixture is concentratedand purified by silica gel column chromatography (MeOH:DCM=1:50) to give268 as an off-white solid (20 mg, 87% yield). (MS: [M+H]585.0)

Step 2: Ex224

A solution of 268 (20 mg, 0.03 mmol) in methanolic HCl (2 M, 5 mL) isstirred at room temperature for 16 hours. The mixture is then filteredand triturated with MeOH (10 mL). The solid is collected by filtrationand dried to give Ex224 as a yellow solid (7 mg, 38% yield). (MS: [M+H]⁺541.0)

The following compounds are prepared by essentially the same method asfor Ex224.

Example Building blocks Structure MS Ex225

[M + H]⁺ 541.0 Ex226

—

Example 227

Step 1: Amine 269

A mixture of E20 (80 mg, 0.2 mmol) in EtOH (3 mL) is addedpicolinaldehyde (36 mg, 0.3 mmol) at room temperature. After stirring at90° C. for 16 hours, the mixture is cooled to room temperature andsodium cyanoborohydride (32 mg, 0.5 mmol) is added. The mixture is thenstirred at room temperature for 1 hour, concentrated, and purified bysilica gel column chromatography (MeOH:DCM=1:50) to give 269 as a yellowsolid (60 mg, 63% yield). (MS: [M+H]⁺ 571.1)

Step 2: Ex227

Following the procedure for Ex224 using 269 (60 mg, 0.1 mmol) and HCl(2M in MeOH, 5 mL) gives Ex227 as a yellow solid (25 mg, 45% yield).(MS: [M+H]⁺ 527.0)

The following compounds are prepared by essentially the same method asfor Ex227.

Example Building blocks Structure MS Ex228

[M + H]⁺ 527.0 Ex229

[M + H]⁺ 492.0

Example 230

Step 1: Ether 270

Following the procedure for 16 using E11 (400 mg, 1.16 mmol), DCM (10mL), 4-pyridineboronic acid (430 mg, 3.49 mmol), Cu(OAc)₂ (253 mg, 1.39mmol), and TEA (588 mg, 5.81 mmol), triturate with EtOH (5 mL) to give270 as a yellow solid (215 mg, 44% yield). (MS: [M+H]⁺ 421.0)

Step 2: Ex230

To a solution of 270 (84.3 mg, 0.2 mmol) in DCM (8 mL) is added borontribromide (100 mg, 0.4 mmol) at −78° C. After stirring at −78° C. for 1hour and then at room temperature overnight, water is added at −30° C.and the mixture is concentrated and purified by prep-HPLC to give Ex230as a white solid (32 mg, 40% yield). (MS: [M+H]⁺ 407.0)

The following compound is prepared by essentially the same method as forEx230.

Example Building blocks Structure MS Ex231

[M + H]⁺ 423.0

Example 232

Step 1: Triazole 271

To a solution of E14 (20 mg, 0.05 mmol) in MeCN (2 mL) is addedazidobenzene (17.3 mg, 0.05 mmol), CuI (18.5 mg, 0.10 mmol), and TEA(14.7 mg, 0.15 mmol). After stirring at room temperature overnight, themixture is filtered, concentrated, and purified by prep-TLC(MeOH:DCM=1:20) to give 271 as a yellow solid (20 mg, 78% yield). (MS:[M+H]⁺ 531.1)

Step 2: Ex232

A solution of 271 (20 mg, 0.04 mmol) in methanolic HCl (2 M, 5 mL) isstirred at 50° C. for 1 hour. The mixture is then concentrated andpurified by prep-TLC (MeOH:DCM=1:20) to give Ex232 as a yellow solid (4mg, 22% yield). (MS: [M+H]⁺487.1)

The following compound is prepared by essentially the same method as forEx232.

Example Building blocks Structure MS Ex233

[M + H]⁺ 488.0

Example 234

Step 1: Ether 272

A mixture of E19 (120 mg, 0.24 mmol), iron powder (68 mg, 1.20 mmol),ammonium chloride (65 mg, 1.20 mmol) in EtOH (20 mL) and water (1 mL) isstirred at 90° C. overnight. After cooling to room temperature, themixture is filtered, concentrated, and purified by silica gel columnchromatography (MeOH:DCM=1:20) to give 272 as a yellow solid (50 mg, 45%yield). (MS: [M+H]⁺ 466.1)

Step 2: Ex234

To a solution of 272 (60 mg, 0.13 mmol) in DCM (3 mL) is added TFA (1.5mL) at 0° C. After stirring at room temperature overnight, the mixtureis concentrated and triturated with MeOH (1 mL). The solid is collectedby filtration and dried to give Ex234 as a yellow solid (10 mg, 19%yield). (MS: [M+H]⁺ 422.0)

The following compounds are prepared by essentially the same method asdescribed above.

Refer- ence of prepa- Example Building blocks Structure MS ration ExA1

[M + H]⁺ 489.0 Ex125 ExA2

[M − H]⁻ 566.0 Ex125 ExA3

[M + H]⁺ 566.0 Ex125 ExA4

[M + H]⁺ 474.0 Ex125 ExA5

[M + H]⁺ 469.0 Ex84 ExA6

[M + H]⁺ 487.9 Ex84 ExA7

[M + H]⁺ 537.0 Ex84 ExA8

[M + H]⁺ 489.0 Ex84 ExA9

[M + H]⁺ 515.0 Ex84 ExA10

[M + H]⁺ 483.0 Ex84 ExA11

[M + H]⁺ 446.0 Ex84 ExA12

[M + H]⁺ 478.0 Ex80 ExA13

[M + H]⁺ 507.0 Ex80 ExA14

[M + H]⁺ 517.0 Ex212 ExA15

[M + H]⁺ 522.0 Ex212 ExA16

[M + H]⁺ 567.9.0 Ex212 ExA17

[M + H]⁺ 455.0 Ex217

Example A18

Step 1: Ether 273

To a solution of E3 (68 mg, 0.17 mmol) and AA2 (50 mg, 0.17 mmol) in THF(3 mL) is added PPh₃ (90 mg, 0.34 mmol) and DIAD (69 mg, 0.34 mmol).After stirring for at room temperature for 4 hours, the mixture isconcentrated and purified by silica gel column chromatography(MeOH:DCM=1:10) to give 273 as a yellow solid (30 mg, 26%). (MS: [M+H]⁺683.0)

Step 2: Pyrimidine 274

To a solution of 273 (30 mg, 0.04 mmol) in DCM (4 mL) and water (2 mL)is added DDQ (20 mg, 0.08 mmol). After stirring at room temperature for4 hours, the mixture is diluted with EA (50 mL), washed with water (10mL), dried over anhydrous sodium sulfate, filtered, concentrated, andpurified by silica gel column chromatography (MeOH:DCM=1:10) to give 274as a yellow solid (15 mg, 65%). (MS: [M+H]⁺ 512.0)

Step 3: ExA18

To a solution of 274 (30 mg, 0.04 mmol) in DCM (4 mL) is added TFA (0.4mL). After stirring at room temperature for 1 hour, the mixture isconcentrated and purified by prep-HPLC to give ExA18 as a yellow solid(4 mg, 29%). (MS: [M+H]⁺ 469.0)

Example A19

Step 1: Ether 275

To a solution of BA4 (71 mg 0.2 mmol) in DMF (5 mL) is added E3 (83.5 mg0.2 mmol) and potassium carbonate (59 mg 0.43 mmol). After stirring atroom temperature for 1 hour, the mixture is concentrated and trituratedwith water (5 mL). The solid is collected by filtration and washed withPE (12 mL) to give 275 as a yellow solid (120 mg 82% yield). (MS: [M+H]⁺683.0)

Step 2: Pyrimidine 276

To a solution of 275 (120 mg, 0.18 mmol) in DCM (10 mL) and water (1 mL)is added DDQ (80 mg 0.35 mmol). After stirring at room temperature for 3hours, the mixture is diluted with water (20 mL) and the aqueous layeris extracted with DCM (20 mL×2). The combined organic layers areconcentrated and purified by prep-TLC (EA:PE=1:1) to give 276 as a lightyellow solid (45 mg, 48%). (MS: [M+H]⁺ 533.0)

Step 3: ExA19

To a solution of 276 (45 mg, 0.08 mmol) in DCM (4 mL) is added TFA (2mL) dropwise at 0° C. After stirring at room temperature for 30 minutes,the mixture is concentrated and triturated with MeCN (5 mL). The solidis collected by filtration and dried to give ExA19 as a light yellowsolid (7 mg, 17% yield). (MS: [M+H]⁺ 491.0)

Example A20

To a solution of ExA10 (45 mg, 0.09 mmol) in DCM is added DAST (145 mg,0.9 mmol) at 0° C. After stirring at room temperature for 30 minutes,the mixture is concentrated, purified by silica gel columnchromatography (MeOH:DCM=1:10), and triturated with MeOH to give ExA20as a solid (10.8 mg, 24%). (MS: [M+H]⁺ 505.0)

Example B1

Step 1: Ester 277

To a solution of E3 (100 mg, 0.25 mmol) in DMF (15 mL) is added NaH (15mg, 0.38 mmol) at 0° C. and stirred for 30 minutes before tert-butyl2-bromoacetate (0.074 mL, 0.38 mmol) is added. After stirring at roomtemperature for 5 hours, water is added and the mixture is extractedwith EA (20 mL×3). The combined organic layers are dried over anhydroussodium sulfate, concentrated, and purified by silica gel columnchromatography (EA:PE=1:10) to give 277 as a yellow solid (100 mg, 77%).(MS: [M+H]⁺ 507.2)

Step 2: Acid 278

To a solution of 277 (100 mg 0.20 mmol) in DCM (10 mL) is added TFA (2mL). After stirring at room temperature for 8 hours, the mixture isconcentrated and triturated with MeOH (1 mL). The solid is collected byfiltration to give 278 (80 mg, 100%). (MS: [M+H]⁺ 407.2)

Step 3: Acyl Chloride 279

To a solution of 278 (80 mg, 0.20 mmol) in MeCN (5 mL) is added thionylchloride (0.044 mL, 0.60 mmol). After stirring at room temperature for10 minutes, the mixture is concentrated to give 279 as an oil (80 mg,96%). (MS: [M+H]⁺ 425.6).

Step 4: ExB1

To a solution of 279 (80 mg, 0.19 mmol), 2-amino-1,3,4-thiadiazole (29mg, 0.29 mmol) in DCM (10 mL) is added TEA (0.053 mL, 0.38 mmol). Afterstirring at 25° C. for 5 hours, the mixture is concentrated and purifiedby pre-HPLC (water:MeOH with 0.1% formic acid=7:1) to give ExB1 as asolid (40 mg, 43%). (MS: [M+H]⁺ 490.2)

Example B2

Step 1: Ether 280

Prepared by essentially the same coupling condition as for CB1. (MS:[M+H]⁺661.1)

Step 2: ExB2

To a solution of 280 (20 mg, 0.03 mmol) in DCM (1 mL) is added TFA (0.1mL). After stirring at room temperature for 4 hours, the mixture isconcentrated and purified by prep-HPLC to give ExB11 as a yellow solid(2.0 mg, 14%). (MS: [M+H]⁺ 467.0)

Example B3

Step 1: Ether 281

Following the procedure for C19 using E3 (44 mg, 0.11 mmol), potassiumcarbonate (31 mg, 0.22 mmol), DMF (5 mL), and B28 (50 mg, 0.11 mmol),react at 70° C. for 3 hours and purify with silica gel columnchromatography (EA:PE=1:2) to give 281 as a yellow solid (25 mg, 35%).(MS: [M+H]⁺ 663.1)

Step 2: ExB3

Prepared by essentially the same method as for C8. (MS: [M+H]⁺ 469.1)

Example B4

Step 1: Ether 282

Following the procedure for C19 using E3 (157 mg, 0.4 mmol), potassiumcarbonate (110 mg, 0.8 mmol), DMF (10 mL), BB2 (100 mg, 0.4 mmol), reactat 60° C. for 3 hours and purify with silica gel column chromatography(EA:PE=1:3) to give 282 as a yellow solid (160 mg, 71%). (MS: [M+H]⁺560.1)

Step 2: Pyrimidine 283

Following the procedure for 57 using 282 (150 mg, 0.27 mmol), TEA (0.07mL, 0.54 mmol), THF (5 mL), and 2,4-dimethoxybenzylamine (44 mg, 0.27mmol), react at room temperature overnight and purify with silica gelcolumn chromatography (EA:PE=1:1) to give 283 as a yellow solid (180 mg,97%). (MS: [M+H]⁺ 691.1)

Step 3: pyrimidine 284

Following the procedure for 276 using 283 (100 mg, 0.14 mmol), DCM (5mL), water (2 mL), DDQ (65 mg, 0.28 mmol), then purify with silica gelcolumn chromatography (EA:PE=1:1) to give 284 as a yellow solid (70 mg,92%). (MS: [M+H]⁺ 541.1)

Step 4: Phenol 285

Prepared by essentially the same method as for C8. (MS: [M+H]⁺ 497.1)

Step 5: ExB4

Following Procedure C using 285 (15 mg, 0.031 mmol), THF (5 mL), andsodium borohydride (1.17 mg, 0.031 mmol), then triturate the crudeproduct with MeCN (5 mL) to give ExB4 as a pale yellow solid (4.5 mg,30% yield). (MS: [M+H]⁺ 499.0)

Example B5

A mixture of CB1 (85 mg, 0.34 mmol), D1 (23 mg, 0.34 mmol) and ammoniumacetate (70 mg, 1.54 mmol) in acetic acid (3 mL) is stirred at 130° C.under microwave irradiation for 45 minutes. After cooling to roomtemperature, the mixture is concentrated and purified by prep-HPLC(water:MeOH with 0.1% formic acid=4:1) to give ExB14 as a yellow solid(30 mg, 30%). (MS: [M+H]⁺ 459.0)

Example B6

Step 2: Ether 286

Prepared by essentially the same method as for C19. (MS: [M+H]⁺ 570.0)

Step 2: Sulfone 287

To a solution of 286 (100 mg, 0.18 mmol) in DCM (5 mL) is added mCPBA(60 mg, 0.36 mmol). After stirring at room temperature for 5 hours, themixture is diluted with EA, washed with saturated sodium thiosulfateaqueous solution, dried over anhydrous anhydrous sodium sulfate,filtered, concentrated, and purified by silica gel column chromatography(EA:PE=1:1) to give 287 as a yellow solid (100 mg, 92%). (MS: [M+H]⁺602.1)

Step 3: Pyrimidine 288

Ammonia is bubbled through to a solution of 287 (100 mg, 0.16 mmol) inTHF (5 mL) at −78° C. for 3 minutes in a sealeding tube. After stirringat room temperature for 3 hours, the mixture is concentrated to give 288as a yellow solid (60 mg, 67%). (MS: [M+H]⁺539.1)

Step 4: ExB6

Prepared by essentially the same method as for C8. (MS: [M+H]⁺ 495.1)

Example B7

Step 1: Ether 290

Prepared by essentially the same method as for 277. (MS: [M+H]⁺ 537.0)

Step 2: ExB7

To a mixture of 290 (200 mg, 0.37 mmol) in 4 N methanolic HCl (3 mL) isadded tin(II) chloride dihydrate (100 mg, 0.44 mmol). After stirring at60° C. for 5 hours, the mixture is cooled to room temperature and thesolid is collected by filteration, dried, washed with MeOH, and purifiedby prep-HPLC (water:MeCN with 0.1% HCOOH=5:1) to give ExB7 as a yellowsolid (10 mg, 6%).

Example B8

Step 1: Ether 291

Prepared by essentially the same method as for Example 125. (MS: [M+H]⁺743.1)

Step 2: Pyrimidine 292

To a mixture of 291 (90 mg, 0.12 mmol) in THF (5 mL) is added sodiumcyanoborohydride (38 mg, 0.61 mmol) at 0° C. After stirring at roomtemperature for 4 hours, water is added and the mixture is extractedwith EA (10 mL). The organic layer is washed with water and brine, driedover anhydrous sodium sulfate, filtered, concentrated and purified bysilica gel column chromatography (EA:PE=1:3) to give 292 as a yellowsolid (30 mg, 33% yield). (MS: [M+H]⁺ 735.1)

Step 3: ExB8

Prepared by essentially the same method as for Ex80. (MS: [M+H]⁺ 510)

Example B9

Step 1: Ether 293

Prepared by essentially the same method as for Ex125. (MS: [M+H]⁺ 605.1)

Step 2: ExB9

To a solution of 293 (86 mg, 0.14 mmol) in EtOH (15 mL) and water (5 mL)is added hydroxylamine hydrochloride (99 mg, 1.42 mmol). After stirringat 100° C. for 24 hours, the mixture is concentrated and purified byprep-HPLC (water:MeCN with 0.1% HCOOH═6:1) to give ExB9 as a white solid(8 mg 12%). (MS: [M+H]⁺ 485.0)

Example B10

Step 1: Ether 295

To a mixture of 294 (200 mg, 0.45 mmol), B19 (250 mg, 0.6 mmo) andsodium iodide (7 mg, 0.045 mmol) in DMF (5 mL) is added potassiumcarbonate (124 mg, 0.9 mmol). After stirring at room temperatureovernight, water is added and the solid is collected by filtration anddried to give 295. (MS: [M+H]⁺ 767.1)

Step 2: ExB10

A solution of 295 (200 mg, 0.45 mmol) in TFA (5 mL) is stirred at roomtemperature for 3 hours. The mixture is then concentrated and purifiedby prep-HPLC (water:MeOH with 0.1% HCOOH=5:1) to give ExB10 (6.4 mg,3%). (MS: [M+H]⁺ 567.0)

Example B11

Step 1: Thiazolidinone 296

Prepared by essentially the same method as for E1.

Step 2: Phenol 297

To a solution of 296 in DCM (10 mL) is added boron tribromide (3 mL) at0° C. After stirring for 3 hours at room temperature, MeOH (10 mL) isadded and the mixture is concentrated and purified by silica gel columnchromatography (MeOH:DCM 1:9) to give 297 (220 mg, 91%). (MS: [M+H]⁺482.2).

Step 3: ExB11

To a solution of 297 (220 mg, 0.44 mmol) in EtOH (10 mL) is addedsaturated ammonium chloride solution (2 mL) and iron powder (246 mg, 4.4mmol). After stirring at 70° C. for 8 hours, the mixture is concentratedand purified by prep-HPLC (water:MeCN with 0.1% formic acid=6:1) to giveExB11 as a solid (200 mg, 99%).

Example B12

Prepared by essentially the same method as for C3.

Example B13

A solution of ExB12 (120 mg, 0.27 mmol) in trimethyl orthoacetate (8 mL)is stirred at 130° C. for 1 hour. After cooling to room temperature, themixture is concentrated and purified by prep-HPLC (water:MeCN with 0.1%formic acid=5:1) to give ExB13 as a solid (20 mg, 16%). (MS: [M+H]⁺463.3)

Example B14

Step 1: thiazolidinone 298

Prepared by essentially the same method as for E1.

Step 2: ExB14

Prepared by essentially the same method as for ExB29.

Example B15

Step 1: Aldehyde 299

Prepared by essentially the same method as for C42. (MS: [M+H]⁺ 342.1)

Step 2: Alkene 300

A mixture of 299 (188 mg, 0.55 mmol), BB7 (318 mg, 0.66 mmol) andpotassium carbonate (152 mg, 1.1 mmol) in DMSO (5 mL) is stirred at 65°C. for 3 hours. The mixture is then diluted with water, acidified to pH5, and extracted with EA (10 mL×3). The combined organic layers aredried over anhydrous sodium sulfate, filtered, concentrated, andpurified by silica gel column chromatography (EA:PE=1:2) to give 300 asa yellow solid (100 mg, 85%). (MS: [M+H]⁺ 464.0)

Step 3: ExB15

To a solution of 300 (100 mg, 0.22 mmol) in EtOH (5 mL) is addedtris(triphenylphosphine)rhodium(I) chloride (20 mg, 0.02 mmol) at roomtemperature. After stirring under a hydrogen atmosphere at 70° C. for 3hours, the mixture is filtered, concentrated. The residue is purified byPre-HPLC (MeCN:H₂O=1:4 with 0.1% HCOOH) to give the titled product (33mg, 33.2%) as a yellow solid. (MS: [M+H]⁺ 466.1)

The following compounds are prepared by essentially the same method asdescribed above.

Refer- ence of Exam- prepa- ple Building blocks Structure MS rationExB16

[M + H]⁺ 381.9 Ex28 ExB17

[M + H]⁺ 403.9 Ex28 ExB18

[M + H]⁺ 358 Ex28 ExB19

[M − H]⁻ 374.0 Ex28 ExB20

[M + H]⁺ 396.2 Ex28 ExB21

[M + H]⁺ 416.0 Ex28 ExB22

[M − H]⁻ 355.0 Ex28 ExB23

[M − H]⁻ 369.1 Ex28 ExB24

[M − H]⁻ 383.3 Ex28 ExB25

[M + H]⁺ 459.0 ExB5 ExB26

[M + H]⁺ 485.0 ExB5 ExB27

[M + H]⁺ 464.0 ExB5 ExB28

[M + H]⁺ 485.0 ExB5 ExB29

[M + H]⁺ 472.0 ExB10 ExB30

[M + H]⁺ 446.0 ExB3 ExB31

[M + H]⁺ 503.7 Ex125 Ex80 ExB32

[M + H]⁺ 486.0 ExB3 Ex80 ExB33

[M + H]⁺ 496.1 C25 ExB34

[M + H]⁺ 454.3 C25 ExB35

[M + H]⁺ 439.1 Ex14 Ex212 Ex220 ExB36

[M + H]⁺ 528.1 ExB3 ExB37

[M + H]⁺ 499.0 Ex212 Ex220 ExB13 ExB38

[M + H]⁺ 482.1 Ex212 ExB39

[M + H]⁺ 455.0 Ex80 ExB40

[M − H]⁻ 446.0 ExB14 ExB41

[M + H]⁺ 435.1 ExB15 ExB42

[M + H]⁺ 453.2 ExB15 ExB43

[M + H]⁺ 464.0 Ex208

Example B44

A solution of ExB31 (209 mg, 1.59 mmol) in saturated ethanolic ammoniasolution (8 mL) is heated at 100° C. under microwave irradiation for 1hour. After cooling to room temperature, the mixture is concentrated andpurified by prep-HPLC (water:MeOH with 0.1% HCOOH=7:1) to give ExB44 asa solid. (20.0 mg, 21%).

Biology

Expression and Purification of Recombinant cGAS Protein

cDNA encoding full-length or amino acids 147-520 of human cGAS isinserted into a modified pET28a vector containing an in-frame His₆-SUMOtag. The E. coli strain BL21/pLys harboring the plasmid is induced with0.5 mM IPTG at 18° C. overnight. His₆-SUMO tag was removed by a SUMOprotease following purification of the His₆-SUMO-cGAS as describedpreviously (Sun et al, 2013, Science 339, 786).

In Vitro Assay for Inhibition of cGAS Activity by Synthetic Compounds

A 40 μL mixture containing 1.5 ng/μL of recombinant cGAS (aa147-522) andserial dilutions of a test compound or DMSO was added to a 96-well plateand incubated at 37° C. for 20 minutes. At the end of reaction, 20 μL ofKinase Glo (Promega) was added and chemiluminescence measured with aluminometer. Inhibitory effect of a compound is evaluated by plottingpercentage of ATP consumption against logarithm of compoundconcentrations. IC₅₀ value was calculated using Graphpad (Sigma).

Inhibition of cGAS enzyme activity in vitro Ex- Act- ample ivity Exl AEx2 C Ex3 A Ex4 C Ex5 A Ex6 C Ex7 C Ex8 C Ex9 C Ex10 C Ex11 C Ex12 AEx13 C Ex14 B Ex15 C Ex16 A Ex17 C Ex18 A Ex19 C Ex20 C Ex21 C Ex22 CEx23 C Ex24 C Ex25 B Ex26 B Ex27 B Ex28 A Ex29 C Ex30 A Ex31 B Ex32 AEx33 B Ex34 B Ex35 B Ex36 C Ex37 B Ex38 A Ex39 B Ex40 B Ex41 B Ex42 BEx43 B Ex44 B Ex45 A Ex46 A Ex47 B Ex48 A Ex49 A Ex50 B Ex51 B Ex52 BEx53 B Ex54 A Ex55 B Ex56 B Ex57 B Ex58 B Ex59 B Ex60 B Ex61 B Ex62 BEx63 A Ex64 B Ex65 A Ex66 B Ex67 B Ex68 A Ex69 B Ex70 B Ex71 A Ex72 AEx73 A Ex74 B Ex75 A Ex76 B Ex77 A Ex78 A Ex79 A Ex80 A Ex81 A Ex82 AEx83 B Ex84 A Ex85 B Ex86 B Ex87 B Ex88 B Ex89 B Ex90 A Ex91 B Ex92 AEx93 A Ex94 B Ex95 B Ex96 B Ex97 B Ex98 B Ex99 B Ex100 C Ex101 B Ex102 BEx103 B Ex104 B Ex105 B Ex106 A Ex107 B Ex108 A Ex109 B Ex110 A Ex111 BEx112 A Ex113 A Ex114 A Ex115 A Ex116 A Ex117 A Ex118 A Ex119 B Ex120 AEx121 A Ex122 A Ex123 A Ex124 A Ex125 B Ex126 B Ex127 B Ex128 B Ex129 BEx130 B Ex131 B Ex132 B Ex133 B Ex134 B Ex135 B Ex136 B Ex137 B Ex138 BEx139 B Ex140 A Ex141 A Ex142 A Ex143 B Ex144 B Ex145 B Ex146 A Ex147 AEx148 A Ex149 B Ex150 B Ex151 B Ex152 A Ex153 A Ex154 B Ex155 A Ex156 AEx157 A Ex158 B Ex159 B Ex160 A Ex161 A Ex162 C Ex163 C Ex164 C Ex165 AEx166 C Ex167 B Ex168 B Ex169 B Ex170 A Ex171 A Ex172 A Ex173 B Ex174 CEx175 B Ex176 B Ex177 B Ex178 B Ex179 B Ex180 B Ex181 B Ex182 B Ex183 BEx184 A Ex185 A Ex186 B Ex187 A Ex188 B Ex189 B Ex190 A Ex191 A Ex192 BEx193 A Ex194 A Ex195 A Ex196 A Ex197 A Ex198 A Ex199 A Ex200 A Ex201 BEx202 B Ex203 B Ex204 B Ex205 B Ex206 B Ex207 B Ex208 B Ex209 B Ex210 BEx211 B Ex212 B Ex213 A Ex214 B Ex215 B Ex216 A Ex217 B Ex218 A Ex219 BEx220 B Ex221 B Ex222 B Ex223 B Ex224 B Ex225 C Ex226 C Ex227 C Ex228 CEx229 C Ex230 C Ex231 B Ex232 C Ex233 C Ex234 C ExA1 A ExA2 A ExA3 AExA4 A ExA5 A ExA6 A ExA7 A ExA8 A ExA9 A ExA10 B ExA11 B ExA12 B ExA13A ExA14 A ExA15 B ExA16 A ExA17 A ExA18 B ExA19 A ExA20 B ExB1 B ExB2 AExB3 A ExB4 A ExB5 C ExB6 B ExB7 C ExB8 C ExB9 B ExB10 B ExB11 C ExB12 CExB13 B ExB14 B ExB15 B ExB16 A ExB17 A ExB18 C ExB19 C ExB20 B ExB21 AExB22 C ExB23 C ExB24 C ExB25 C ExB26 C ExB27 C ExB28 C ExB29 A ExB30 BExB31 B ExB32 A ExB33 C ExB34 C ExB35 A ExB36 C ExB37 A ExB38 C ExB39 BExB40 A ExB41 B ExB42 A ExB43 A ExB44 A Acitivity code: A IC₅₀ ≤0.5 μM,B IC₅₀ 0.5-10 μM, C IC₅₀ ≥10 μMCellular Assay to Detect Inhibition of cGAS Activity by SyntheticCompounds in a Human Monocyte Cell Line

A reporter THP1 cell line harboring a gene encoding Gaussia Luciferaseunder the control of 5 tandem repeats of interferon-stimulated responseelements (ISRE) was used to test inhibition of cGAS activity bysynthetic compounds in human cells. These cells were plated on 96-wellplates at 0.3×10⁶/well and incubated with various concentrations ofcompounds or DMSO for 5 min, followed by transfection of 2 μg/mL of ISD(Interferon Stimulatory DNA, a 45 bp DNA oligo) or mock transfectedusing lipofectamine 2000 (Life Technology) method, according tomanufacturer's instructions. 16 hours later, 15 μL of the media fromeach well is transferred to a new plate, 50 μL of solution containing 50mM Hepes-NaOH, 50 mM NaCl, 10 mM EDTA, 1 μM of coeleanterazine was addedto each well and luminescence was measured immediately. Fold increase inluminescence compared to mock transfection is plotted againstconcentrations of each compound, and IC₅₀ is calculated using Graphpad.To evaluate the specificity of a compound, the same procedure wasperformed except that cells were transfected with 2 μg/mL poly(I:C) orinfected with Sendai Virus (SeV) at 50 Unit/mL, which are known toactivate the RIG-I-MAVS pathway. A specific inhibitory compound shouldinhibit interferon induction by DNA but have minimal effect on poly(I:C)or Sendai virus induced interferon reporter gene expression.

Inhibition of cGAS activity in THP1 cells Example THP1-ISD THP1-SeV Ex11B NT Ex16 B NT Ex21 B NT Ex28 A C Ex30 A NT Ex32 A NT Ex33 B NT Ex38 BNT Ex39 B NT Ex44 A NT Ex45 B NT Ex53 A NT Ex57 A B Ex61 A NT Ex63 B CEx65 B C Ex67 B NT Ex68 A C Ex70 B C Ex73 B C Ex75 B C Ex80 B C Ex81 A CEx82 A NT Ex86 B B Ex87 B C Ex90 B NT Ex92 A C Ex93 B C Ex106 B NT Ex107B NT Ex108 A C Ex110 A NT Ex112 B NT Ex113 B NT Ex114 B NT Ex115 B NTEx116 A NT Ex117 B NT Ex122 A C Ex123 A C Ex124 B NT Ex131 B B Ex135 B CEx137 B C Ex139 B C Ex140 A C Ex141 A C Ex147 A C Ex148 A C Ex149 A CEx152 A C Ex153 B C Ex155 B C Ex156 B C Ex157 B C Ex165 B C Ex170 A CEx171 B C Ex177 B C Ex184 A C Ex185 B NT Ex189 B NT Ex193 B C Ex194 A CEx195 B C Ex196 A C Ex197 B C Ex200 A C Ex211 B C Ex213 B C Ex216 A BEx233 B C Ex234 B C ExAl B C ExA2 C C ExA3 B C ExA4 A C ExA5 B NT ExA6 BB ExA7 B C ExA9 B NT ExA10 B NT ExA11 A NT ExA12 C NT ExA13 B NT ExA14 CNT ExA15 B C ExA17 C NT ExA18 C NT ExA19 B NT ExB21 B C ExB2 A C ExB3 AC ExB4 C C ExB35 A C ExB40 B C ExB43 C C ExB44 B C Acitivity code: AIC₅₀ ≤2.5 μM, B IC₅₀ 2.5-10 μM, C IC₅₀ ≥10 μM NT not tested

The invention claimed is:
 1. A compound, wherein the compound is one ofFormula Ic:

wherein: X is NH or S; Y is O or S; Z is O, S, CHR^(1a) or NR^(1a);wherein R^(1a) is hydrogen, C₁₋₆alkyl, or C₁₋₆alkyl selectivelyfunctionalized with one or more halogen, thiol, hydroxyl, carbonyl,carboxyl, carbonyloxyl, C₁₋₆alkoxy, C₁₋₆hydroxyalkoxy, amino,C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, or azido groups; G is N or C; if Gis N, then R¹ is C₁₋₆alkyl or C₁₋₆alkyl selectively functionalized withone or more halogen, thiol, hydroxyl, carbonyl, carbonyloxyl,C₁₋₆alkoxy, C₁₋₆hydroxyalkoxy, amino, C₁₋₆alkylamino,di(C₁₋₆alkyl)amino, or azido groups, or R¹-R^(1a) are connected as a—CH₂CH₂—, —CH₂CH₂CH₂—, —CH═CH—, —C(CH₃)═CH— or —CH═C(CH₃)— group; and ifG is C, then Z includes R^(1a) and R¹-R^(1a) are connected as a═CH—CH═CH—, ═N—CH═CH—, or ═CH—N═CH— group; W is OR^(10a) or NHR^(10a);wherein R^(10a) is hydrogen, C₁₋₆alkyl, or C₁₋₆alkyl selectivelyfunctionalized with one or more halogen, thiol, hydroxyl, carbonyl,carboxyl, carbonyloxyl, C₁₋₆alkoxy, C₁₋₆hydroxyalkoxy, amino,C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, or azido groups, or R^(10a)-R⁶ areconnected as a —CH₂—CH₂—, —CH═CH—, —N═CH—, or —CH═N— group; R² ishydrogen, halogen, C₁₋₆alkyl, or C₁₋₆alkyl selectively functionalizedwith one or more halogen, thiol, hydroxyl, carbonyl, carboxyl,carbonyloxyl, C₁₋₆alkoxy, C₁₋₆hydroxyalkoxy, amino, C₁₋₆alkylamino,di(C₁₋₆alkyl)amino, or azido groups; R³ is halogen, —SR^(3a),—S(O)R^(3a), —OR^(3a), —OCH₂R^(3b), —OCH(CH₃)R^(3b), —OC(O)NHR^(3a),—NR^(3a)R^(4a), —NHSO₂R^(3a), azido, —CHO, —CO₂R^(3a), cyano, C₁₋₆alkyl,—CR^(5a)R^(6a)R^(7a), C₂₋₆alkenyl, —C(R^(5a))═C(R^(8a))(R^(9a)),C₂₋₆alkynyl, —C≡CR^(8a), or R²—R³ are connected as a —CH₂CH₂—or—CH₂CH₂CH₂— group; wherein R^(3a), R^(3b), and R^(4a) are independentlyhydrogen, phenyl, naphthyl, pyridyl, pyrimidinyl, imidazolyl,1,2,3-triazolyl, quinolinyl, isoquinolinyl, thiazolyl, tetrazolylgroups, C₁₋₆alkyl, cyclic-(C₁₋₈alkyl)-, cyclic-(C₁₋₆oxaalkyl)-,cyclic-(C₁₋₆azaalkyl)-, C₂₋₆alkenyl, or C₂₋₆alkynyl; wherein the phenyl,naphthyl, pyridyl, pyrimidinyl, imidazolyl, 1,2,3-triazolyl, quinolinyl,isoquinolinyl, thiazolyl, or tetrazolyl groups are optionallysubstituted with 1-3 substituents independently selected from the groupconsisting of halogen, thiol, C₁₋₆alkyl thioether, C₁₋₆alkyl sulfoxide,C₁₋₆alkyl, C₁₋₆alkoxyl, amino, C₁₋₆alkylamino, C₁₋₆dialkylamino,C₁₋₆alkyl sulfonamide, azido, —CHO, —CO₂H, C₁₋₆alkyl carboxylate, cyano,C2-6alkenyl, and C₂₋₆alkynyl group; and the C₁₋₆alkyl,cyclic-(C₁₋₈alkyl)-, cyclic-(C₁₋₆oxaalkyl)-, cyclic-(C₁₋₆azaalkyl)-,C₂₋₆alkenyl, or C₂₋₆alkynyl groups are selectively functionalized withone or more halogen, thiol, hydroxyl, carbonyl, carboxyl, carbonyloxyl,C₁₋₆alkoxy, C₁₋₆hydroxyalkoxy, amino, C₁₋₆alkylamino,di(C₁₋₆alkyl)amino, azido, piperidinyl, phenyl, naphthyl, pyridyl,pyrimidinyl, imidazolyl, 1,2,3-triazolyl, quinolinyl, isoquinolinyl,thiazolyl, or tetrazolyl groups; wherein R^(5a), R^(6a), R^(7a), R^(8a),and R^(9a) are independently hydrogen, phenyl, naphthyl, pyridyl,pyrimidinyl, imidazolyl, 1,2,3-triazolyl, quinolinyl, isoquinolinyl,thiazolyl, tetrazolyl groups, C₁₋₆alkyl, cyclic-(C₁₋₈alkyl)-,cyclic-(C₁₋₆oxaalkyl)-, cyclic-(C₁₋₆azaalkyl)-, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆alkoxyl, cyclic-(C₁₋₈alkoxyl)-,cyclic-(C₁₋₆oxaalkoxyl)-, or cyclic-(C₁₋₆azaalkoxyl)-; wherein thephenyl, naphthyl, pyridyl, pyrimidinyl, imidazolyl, 1,2,3-triazolyl,quinolinyl, isoquinolinyl, or thiazolyl, tetrazolyl groups areoptionally substituted with 1-3 substituents independently selected fromthe group consisting of halogen, thiol, C₁₋₆alkyl thioether, C₁₋₆alkylsulfoxide, C₁₋₆alkyl, C₁₋₆alkoxyl, amino, C₁₋₆alkylamino,C₁₋₆dialkylamino, C₁₋₆alkyl sulfonamide, azido, —CHO, —CO₂H, C₁₋₆alkylcarboxylate, cyano, C₂₋₆alkenyl, and C₂₋₆alkynyl groups; and theC₁₋₆alkyl, cyclic-(C₁₋₈alkyl)-, cyclic-(C₁₋₆oxaalkyl)-,cyclic-(C₁₋₆azaalkyl)-, C₂₋₆alkenyl, or C₂₋₆alkynyl groups areselectively functionalized with one or more halogen, thiol, hydroxyl,carbonyl, carboxyl, carbonyloxyl, C₁₋₆alkoxy, C₁₋₆ hydroxyalkoxy, amino,C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, azido, piperidinyl, phenyl,naphthyl, pyridyl, pyrimidinyl, imidazolyl, 1,2,3-triazolyl, quinolinyl,isoquinolinyl, thiazolyl, or tetrazolyl groups; R⁶ is hydrogen, halogen,—SR^(3a), —S(O)R^(3a), —OR^(3a), —OCH₂R^(3b), —OCH(CH₃)R^(3b),—OC(O)NHR^(3a), —NR^(3a)R^(4a), —NHSO₂R^(3a), azido, —CHO, CO₂R^(3a),cyano, C₁₋₆alkyl, —CR^(5a)R^(6a)R^(7a), C₂₋₆alkenyl,—C(R^(5a))═C(R^(8a))(R^(9a)), C₂₋₆alkynyl, or —C≡CR^(8a); whereinR^(3a), R^(3b), and R^(4a) are independently hydrogen, phenyl, naphthyl,pyridyl, pyrimidinyl, imidazolyl, 1,2,3-triazolyl, quinolinyl,isoquinolinyl, thiazolyl, tetrazolyl groups, C₁₋₆alkyl,cyclic—(C₁₋₈alkyl)—, cyclic—(C₁₋₆oxaalkyl)—, cyclic—(C₁₋₆azaalkyl)—,C₂₋₆alkenyl, or C₂₋₆alkynyl; wherein the phenyl, naphthyl, pyridyl,pyrimidinyl, imidazolyl, 1,2,3—triazolyl, quinolinyl, isoquinolinyl,thiazolyl, or tetrazolyl groups are optionally substituted with 1-3substituents independently selected from the group consisting ofhalogen, thiol, C₁₋₆alkyl thioether, C₁₋₆alkyl sulfoxide, C₁₋₆alkyl,C₁₋₆alkoxyl, amino, C₁₋₆alkylamino, C₁₋₆dialkylamino, C₁₋₆alkylsulfonamide, azido, —CHO, —CO₂H, C₁₋₆alkyl carboxylate, cyano,C₂₋₆alkenyl, and C₂₋₆alkynyl group; and the C₁₋₆alkyl,cyclic—(C₁₋₈alkyl)—, cyclic—(C₁₋₆oxaalkyl)—, cyclic—(C₁₋₆azaalkyl)—,C₂₋₆alkenyl, or C₂₋₆alkynyl groups are selectively functionalized withone or more halogen, thiol, hydroxyl, carbonyl, carboxyl, carbonyloxyl,C₁₋₆alkoxy, C₁₋₆hydroxyalkoxy, amino, C₁₋₆alkylamino,di(C₁₋₆alkyl)amino, azido, piperidinyl, phenyl, naphthyl, pyridyl,pyrimidinyl, imidazolyl, 1,2,3—triazolyl, quinolinyl, quinolinyl,isoquinolinyl, thiazolyl, or tetrazolyl groups; wherein R^(5a), R^(6a),R^(7a), R^(8a), and R^(9a) are independently hydrogen, phenyl, naphthyl,pyridyl, pyrimidinyl, imidazolyl, 1,2,3—triazolyl, quinolinyl,isoquinolinyl, thiazolyl, tetrazolyl groups, C₁₋₆alkyl,cyclic—(C₁₋₈alkyl)—, cyclic—(C₁₋₆oxaalkyl)—, cyclic—(C₁₋₆azaalkyl)—,C₂₋₆alkenyl, C₂₋₆alkynyl, C₂₋₆alkynyl, C₁₋₆alkoxyl,cyclic—(C₁₋₈alkoxyl)—, cyclic—(C₁₋₆oxaalkoxyl)—, orcyclic—(C₁₋₆azaalkoxyl)—; wherein the phenyl, naphthyl, pyridyl,pyrimidinyl, imidazolyl, 1,2,3—triazolyl, quinolinyl, isoquinolinyl, orthiazolyl, tetrazolyl groups are optionally substituted with 1-3substituents independently selected from the group consisting ofhalogen, thiol, C₁₋₆alkyl thioether, C₁₋₆alkyl sulfoxide, C₁₋₆alkyl,C₁₋₆alkoxyl, amino, C₁₋₆alkylamino, C₁₋₆diakylamino, C₁₋₆alkylsulfonamide, azido, —CHO, —CO₂H, C₁₋₆alkyl carboxylate, cyano,C₂₋₆alkenyl, and C₂₋₆alkynyl groups; and the C₁₋₆alkyl,cyclic—(C₁₋₈alkyl)—, cyclic—(C₁₋₆oxaalkyl)—, cyclic—(C₁₋₆azaalkyl)—,C₂₋₆alkenyl, or C₂₋₆alkynyl groups are selectively functionalized withone or more halogen, thiol, hydroxyl, carbonyl, carboxyl, carbonyloxyl,C₁₋₆alkoxy, C₁₋₆hydroxyalkoxy, amino, C₁₋₆alkylamino,di(C₁₋₆alkyl)amino, azido, piperidinyl, phenyl, naphthyl, pyridyl,pyrimidinyl, imidazolyl, 1,2,3—triazolyl, quinolinyl, isoquinolinyl,thiazolyl, or tetrazolyl groups; R⁴ is hydrogen or halogen; or apharmaceutically acceptable salt thereof.
 2. The compound of claim 1,wherein X is S; Z is O or S; and G is N; and R¹ is C₁₋₆alkyl orC₁₋₆alkyl selectively functionalized with one or more halogen, thiol,hydroxyl, carbonyl, carbonyloxyl, C₁₋₆alkoxy, C₁₋₆hydroxyalkoxy, amino,C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, or azido groups; or G is N; Z isNR^(1a); and R¹-R^(1a) are connected as a —CH₂CH₂—, —CH₂CH₂CH₂—,—CH═CH—, —C(CH₃)═CH—, or —CH═C(CH₃)— group; or G is C; Z is NR^(1a); andR¹-R^(1a) are connected as a═CH—CH═CH—, ═N—CH═CH—, or ═CH—N═CH— group.3. The compound of claim 1, wherein the compound is one of Formula Id:

wherein: R³ is halogen.
 4. The compound of claim 3, wherein Z is O or S;and G is N; and R¹ is C₁₋₆alkyl or C₁₋₆alkyl selectively functionalizedwith one or more halogen, thiol, hydroxyl, carbonyl, carboxyl,carbonyloxyl, C₁₋₆alkoxy, C₁₋₆hydroxyalkoxy, amino, C₁₋₆alkylamino,di(C₁₋₆alkyl)amino, or azido groups; or G is N; Z is NR^(1a); andR¹-R^(1a) are connected as a —CH₂CH₂—, —CH₂CH₂CH₂—, —CH═CH—,—C(CH₃)═CH—, or —CH═C(CH₃)— group; or G is C; Z is NR^(1a); andR¹-R^(1a) are connected as a═CH—CH═CH—, ═N—CH═CH—, or ═CH—N═CH— group.5. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 6. A compound is selectedfrom the group consisting of:

or a pharmaceutically acceptable salt thereof.
 7. A pharmaceuticalcomposition comprising a compound of claim 1, and a pharmaceuticallyacceptable carrier.
 8. The compound of claim 1, wherein X is S; Y is O;and Z is O.
 9. The compound of claim 8, wherein G is N.
 10. The compoundof claim 9, wherein R¹ is C₁₋₆alkyl.
 11. The compound of claim 10,wherein R¹ is methyl.
 12. The compound of claim 9, wherein R¹ isC₁₋₆alkyl functionalized with one or more halogen, thiol, hydroxyl,carboxyl, carbonyloxyl, C₁₋₆alkoxy, C₁₋₆hydroxyalkoxy, amino,C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, or azido groups.
 13. The compound ofclaim 9, wherein R³ is halogen.
 14. The compound of claim 13, wherein R⁴is hydrogen.
 15. The compound of claim 1, wherein X is S; Y is O or S; Gis N; Z is NR^(1a); and R¹-R^(1a) are connected as a —CH₂CH₂—,—CH₂CH₂CH₂—, —CH═CH—, —C(CH₃)═CH—, or —CH═C(CH₃)— group.
 16. Thecompound of claim 15, wherein Y is O.
 17. The compound of claim 1,wherein X is S; Y is O or S; G is C; Z is NR^(1a); and R¹-R^(1a) areconnected as a═CH—CH═CH—, ═N—CH═CH—, or ═CH—N═CH— group.
 18. Thecompound of claim 17, wherein Y is O.
 19. The compound of claim 1,wherein R² is hydrogen, Cl, Br, or methyl.
 20. The compound of claim 19,wherein R² is hydrogen.
 21. The compound of claim 6, wherein thecompound is

or a pharmaceutically acceptable salt thereof.
 22. The compound of claim6, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 23. The compound of claim6, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 24. The compound of claim6, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 25. The compound of claim6, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 26. The compound of claim6, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 27. The compound of claim6, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 28. The compound of claim1, wherein R³ is halogen.
 29. The compound of claim 1, wherein R³ is Br.30. The compound of claim 1, wherein R⁴ is hydrogen.
 31. The compound ofclaim 1, wherein R⁴ is halogen.
 32. The compound of claim 1, wherein R⁴is F.
 33. The compound of claim 3, wherein R³ is Br.
 34. The compound ofclaim 3, wherein R⁴ is hydrogen.
 35. The compound of claim 3, wherein R⁴is halogen.
 36. The compound of claim 3, wherein Z is O.
 37. Thecompound of claim 1, wherein Z is O, CHR^(1a) or NR^(1a).
 38. Thecompound of claim 1, wherein Z is O.
 39. The compound of claim 1,wherein X is S.
 40. The compound of claim 1, wherein Y is O.
 41. Thecompound of claim 1, wherein Y is O, and Z is O.
 42. The compound ofclaim 1, wherein R⁶ is —OR^(3a).
 43. The compound of claim 42, whereinR^(3a) is C₁₋₆alkyl.
 44. The compound of claim 42, wherein R^(3a) isC₁₋₆alkyl selectively functionalized with one or more halogen, thiol,hydroxyl, carbonyl, carboxyl, carbonyloxyl, C₁₋₆alkoxy,C₁₋₆hydroxyalkkoxy, amino, C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, azido,piperidinyl, phenyl, naphthyl, pyridyl, pyrimidinyl, imidazolyl,1,2,3—triazolyl, quinolinyl, isoquinolinyl, thiazolyl, or tetrazolylgroups.
 45. The compound of claim 44, wherein R^(3a) is C₁₋₆alkylselectively functionalized with a pyrimidinyl group.
 46. The compound ofclaim 44, wherein R^(3a) is C₁₋₆alkyl selectively functionalized with apyridyl group.